tag:blogger.com,1999:blog-55361872286567525472024-03-04T23:51:22.614-08:00Bugbank NewsDaniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.comBlogger19125tag:blogger.com,1999:blog-5536187228656752547.post-18684267734084808832022-01-26T02:33:00.002-08:002022-01-26T02:33:35.556-08:00News now archived<p> The news feed below is an archive.</p>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-64940645680998126352020-09-24T01:43:00.002-07:002020-09-24T01:43:13.390-07:00Weekly feed in response to uptick in cases in England<p>As the number of cases in England is rising, <a href="https://news.sky.com/story/coronavirus-r-number-increases-to-between-1-1-and-1-4-12075062">with a reproduction number above 1</a>, we will resume providing weekly feeds of swab test results from Public Health England to UK Biobank and the other cohorts.</p>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-7511730109869811472020-08-21T07:23:00.006-07:002020-08-21T07:23:59.734-07:00Presentation on identifying COVID-19 inpatients from Public Health England data<p>This is a presentation I gave at the <a href="https://www.covid19hg.org">COVID-19 Host Genetics Initiative</a> meeting on <a href="https://www.covid19hg.org/blog/2020-07-02-july-2-2020-meeting/">2nd July 2020</a> about using Public Health England's Second Generation Surveillance System to identify COVID-19 inpatients among SARS-CoV-2 positive individuals in England.</p><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/BySQxUMZWRo" width="320" youtube-src-id="BySQxUMZWRo"></iframe></div><p>For further information, please see this <a href="https://news.bugbank.uk/2020/08/identifying-inpatients-comparison-to.html">bugbank blog post</a> comparing inpatients identified using SGSS and Hospital Episode Statistics.</p>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-73634403166852394172020-08-19T01:54:00.000-07:002020-08-19T01:54:03.564-07:00Identifying inpatients: comparison to Hospital Episode Statistics<p><span style="font-family: "Times New Roman", serif;">Since April, the <a href="http://www.bugbank.uk/">bugbank project</a> </span><span style="font-family: "Times New Roman", serif;">has fed information on SARS-CoV-2 PCR-based swab tests to <a href="https://www.ukbiobank.ac.uk">UK Biobank</a> (UKB) and other cohorts from Public Health England (PHE)’s Second Generation Surveillance System (SGSS). The lag in this database is very short (around 4 days, closer to 10 days by the time it reaches UKB researchers) allowing agile analysis of risk factors. However, there are a range of limitations, including a lack of clinical information. Since a primary research goal is to understand why some people suffer severe COVID-19 from SARS-CoV-2 infection, we sought to identify a subset of SARS-CoV-2 positive individuals that was enriched for hospital inpatients, and therefore enriched for severe disease</span><span style="font-family: "Times New Roman", serif;">. Inpatient status is not directly recorded in SGSS, and nor can it be because often tests are ordered before a decision to admit, e.g. in the emergency department. Therefore we tried to identify inpatients <b>indirectly</b> using available information</span><span style="font-family: "Times New Roman", serif;"> (</span><a href="https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000397" style="font-family: "Times New Roman", serif;">Armstrong et al. 2020</a><span style="font-family: "Times New Roman", serif;">)</span><span style="font-family: "Times New Roman", serif;">. The aim of this post is to assess the performance of that approach.</span></p><style class="WebKit-mso-list-quirks-style">
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</style><p class="MsoNormal" style="font-size: medium;"><o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Working assumptions<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;">There are two key assumptions underlying the approach:<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -18.0pt;"><!--[if !supportLists]-->1.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span><!--[endif]-->SARS-CoV-2 positive inpatients are enriched for severe COVID-19.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Starting around 27 April 2020, English hospitals began routine screening for SARS-CoV-2 infection among inpatients. Before this date, when testing capacity was limited and testing was focused on suspected cases, we consider assumption (1) to be reasonable. After late April, we consider it to be questionable, so the focus here is on the period 16 March (when hospitalization was restricted to severe cases only) to 30 April (46 days).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -18.0pt;"><!--[if !supportLists]-->2.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span><!--[endif]-->Inpatients can be identified indirectly from other data.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">SGSS is a microbiology database, so information on whether a test subject was hospitalized can only be inferred indirectly. The fields we used to infer inpatient status (all of which are now available in the UKB <span style="font-family: Courier; font-size: 10pt;"><a href="http://biobank.ndph.ox.ac.uk/ukb/field.cgi?id=40100">covid19_result</a> </span>table) are:<o:p></o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l3 level1 lfo2; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->The ‘Acute Trust’ flag (<span style="font-family: Courier; font-size: 10pt;">acute</span>), meaning that the test came from a healthcare institution delivering emergency care,<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l3 level1 lfo2; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->The ‘Hospital Acquired Infection’ flag (<span style="font-family: Courier; font-size: 10pt;">hosaq</span>) and <o:p></o:p></p><p class="MsoListParagraphCxSpLast" style="mso-list: l3 level1 lfo2; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->The Requesting Organization Type associated with the test (<span style="font-family: Courier; font-size: 10pt;">reqorg</span>).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Previously proposed inpatient indicators<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;">In the <a href="https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000397">paper</a>, we considered two indicators:<o:p></o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l2 level1 lfo3; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->A more <b>specific</b> method: <span style="font-family: Courier; font-size: 10pt;">reqorg==1</span> (<a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=3311">Hospital inpatient</a>)<o:p></o:p></p><p class="MsoListParagraphCxSpLast" style="mso-list: l2 level1 lfo3; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->A more <b>sensitive</b> method: (<span style="font-family: Courier; font-size: 10pt;">reqorg==1 OR reqorg==5</span> (<a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=3311">Hospital A&E</a>)<span style="font-family: Courier; font-size: 10pt;"> OR acute==1 OR hosaq==1) AND reqorg!=4</span> (<a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=3311">Healthcare worker testing</a>)<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;">The second, more sensitive method, recorded in the <span style="font-family: Courier; font-size: 10pt;">origin</span> column of UKB’s <span style="font-family: Courier; font-size: 10pt;">covid19_result</span> table, was the method we recommended because we preferred to trade off specificity for more cases.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Hospital Episode Statistics as a gold standard<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;">Assessing the indirect identification of inpatients requires an independent source of reliable information. This is now possible using <a href="https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episode-statistics">Hospital Episode Statistics</a> (HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">HES offer a comprehensive source of data on <i>spells</i> of continuous stay in hospital, <i>episodes</i> under the care of each consultant within those spells, and <i>diagnoses</i>. The lag for HES is around three months. Mid-August saw the release by UKB of HES data for England up to 31 May 2020, with a warning that the last month may be <a href="http://biobank.ndph.ox.ac.uk/showcase/exinfo.cgi?src=Data_providers_and_dates">less complete</a> than previous months. Censoring is important because only ‘finished consultant episodes’ are recorded in HES. Length of hospital stay for COVID-19 in the UK in March and April was typically under 30 days, with a median of 14 days, but exceeded 60 days for some patients (<a href="https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30316-7/fulltext">Karagiannidis et al. 2020</a>). The latest HES data are therefore likely to be fairly complete but not definitive for the period of interest (16 March to 30 April).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Assessing Performance<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;">We performed three comparisons of HES and SGSS data, treating HES as the gold standard, restricting attention to 16 March to 30 April, and excluding UKB participants not resident in England or lost to follow-up:<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l5 level1 lfo4; text-indent: -18.0pt;"><!--[if !supportLists]--><i>1.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; font-style: normal; line-height: normal;"> </span></i><!--[endif]--><i>Detection of inpatients<o:p></o:p></i></p><p class="MsoListParagraphCxSpLast" style="margin-left: 72.0pt; mso-add-space: auto; mso-list: l5 level2 lfo4; text-indent: -18.0pt;"><!--[if !supportLists]-->a.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span><!--[endif]--><b>For all participants with a SARS-CoV-2 test</b>, inpatient status (from SGSS) versus inpatient status (from HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l5 level1 lfo4; text-indent: -18.0pt;"><!--[if !supportLists]--><i>2.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; font-style: normal; line-height: normal;"> </span></i><!--[endif]--><i>Detection of COVID-19 diagnosed inpatients<o:p></o:p></i></p><p class="MsoListParagraphCxSpMiddle" style="margin-left: 72.0pt; mso-add-space: auto; mso-list: l5 level2 lfo4; text-indent: -18.0pt;"><!--[if !supportLists]-->a.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span><!--[endif]--><b>For all participants</b>, SARS-CoV-2 positive inpatient status (from SGSS) versus inpatient diagnosis codes for COVID-19 (from HES).<o:p></o:p></p><p class="MsoListParagraphCxSpLast" style="margin-left: 72.0pt; mso-add-space: auto; mso-list: l5 level2 lfo4; text-indent: -18.0pt;"><!--[if !supportLists]-->b.<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span><!--[endif]--><b>For all participants with a positive SARS-CoV-2 test</b>, inpatient status (from SGSS) versus inpatient diagnosis codes for COVID-19 (from HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Comparison 1a differs in that it does not require diagnosis codes for COVID-19 in HES, only the presence of a hospital episode. This tests the stated aim of distinguishing inpatients from non-inpatients among all those participants tested for SARS-CoV-2.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Comparisons 2a and 2b use ICD10 diagnosis codes U071 or U072 to define diagnosis of COVID-19 inpatients in HES. This tests the implied aim of identifying inpatients specifically suffering from COVID-19. Two baseline populations are considered: all participants, and SARS-CoV-2 positive participants.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Both the specific (<span style="font-family: Courier; font-size: 10pt;">reqorg==1</span>) and sensitive (<span style="font-family: Courier; font-size: 10pt;">origin==1</span>) methods of identifying inpatients in SGSS were assessed.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">For each comparison, a two-by-two contingency table was constructed with each element corresponding to counts of UKB participants. The following performance metrics are reported, where truth is determined by HES and discovery is determined by SGSS data:<o:p></o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l4 level1 lfo6; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]--><b>Sensitivity</b>: % true discoveries among all true inpatients<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l4 level1 lfo6; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]--><b>Specificity</b>: % true non-discoveries among all true non-inpatients<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l4 level1 lfo6; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]--><b>Positive predictive value (PPV)</b>: % true discoveries among all discoveries<o:p></o:p></p><p class="MsoListParagraphCxSpLast" style="mso-list: l4 level1 lfo6; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]--><b>Negative predictive value (NPV)</b>: % true non-discoveries among all non-discoveries<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Other methodological details:<o:p></o:p></p><p class="MsoListParagraphCxSpFirst" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->English residence was determined by recruitment centre.<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Tests outside 16 March to 30 April were ignored.<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Hospital spells ending before 16 March or beginning after 30 April were ignored.<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Hospital spells with incomplete admission or discharge dates were ignored.<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Hospital spells with patient classes other than <span style="font-family: courier; font-size: small;">classpat_uni==1000</span> (inpatient) were ignored.<o:p></o:p></p><p class="MsoListParagraphCxSpMiddle" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->In the first pass, the date of the test and the date of the hospital spell were not required to overlap. This decision is scrutinized below.<o:p></o:p></p><p class="MsoListParagraphCxSpLast" style="mso-list: l1 level1 lfo5; text-indent: -18.0pt;"><!--[if !supportLists]--><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->In comparisons 2a and 2b, the identification of SARS-CoV-2 inpatient status from SGSS requires that the positive result and inpatient flag coincide on the same test.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Results<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;"><b>1a. For all participants with a SARS-CoV-2 test</b>, inpatient status (from SGSS) versus inpatient status (from HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><div align="center"><table border="0" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none;"><tbody><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(origin==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(reqorg==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 23.8pt;"><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Tested inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Tested other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Tested inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Tested other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="break-inside: avoid; height: 18.25pt;"><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Any inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">1499<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">377<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">80%<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Any inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">844<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">1032<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">45%<o:p></o:p></span></p></td></tr><tr style="height: 21.75pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">641<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">575<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">47%<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">140<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">1076<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">88%<o:p></o:p></span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">70%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">60%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">86%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">51%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr></tbody></table></div><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Baseline PPV: 61% of participants with a SARS-CoV-2 test were inpatients (by HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;"><b>2a. For all participants</b>, SARS-CoV-2 positive inpatient status (from SGSS) versus COVID-19-diagnosed inpatient status (from HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><div align="center"><table border="0" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; width: 643px;"><tbody><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(origin==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(reqorg==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 23.8pt;"><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-CoV-2 + inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-CoV-2 + inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="break-inside: avoid; height: 18.25pt;"><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">COVID-19 inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">557<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">253<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">69%<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">COVID-19 inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">289<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">521<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">36%<o:p></o:p></span></p></td></tr><tr style="height: 21.75pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">262<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">425821<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">100%<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">62<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">426021<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">100%<o:p></o:p></span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">68%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">100%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">82%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">100%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr></tbody></table></div><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Baseline PPV: 0.2% of all participants were COVID-19-diagnosed inpatients (by HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;"><b>2b. For all participants with a positive SARS-CoV-2 test</b>, inpatient status (from SGSS) versus COVID-19-diagnosed inpatient status (from HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><div align="center"><table border="0" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; width: 643px;"><tbody><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(origin==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td colspan="2" style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">SGSS<o:p></o:p></span></b></p><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 6pt;">(reqorg==1)<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 23.8pt;"><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-2 +ve inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-2 +ve other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-2 +ve inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">SARS-2 +ve other<o:p></o:p></span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 23.8pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="break-inside: avoid; height: 18.25pt;"><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">COVID-19 inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">557<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">69<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">89%<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td rowspan="2" style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="margin-bottom: 0.0001pt; margin-left: 5.65pt; margin-right: 5.65pt; text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">HES<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">COVID-19 inpatient<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">289<o:p></o:p></span></b></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">337<o:p></o:p></span></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Sens<o:p></o:p></span></b></p></td><td style="height: 18.25pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">46%<o:p></o:p></span></p></td></tr><tr style="height: 21.75pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">262<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">221<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">46%<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">Other<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">62<o:p></o:p></span></p></td><td style="border: none; height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">421<o:p></o:p></span></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">Spec<o:p></o:p></span></b></p></td><td style="height: 21.75pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">87%<o:p></o:p></span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">PPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-family: Helvetica; font-size: 8pt;">NPV<o:p></o:p></span></b></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr><tr style="height: 11.5pt;"><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">68%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">76%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">82%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;">56%<o:p></o:p></span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td><td style="height: 11.5pt; padding: 0cm 5.4pt;"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 8pt;"> </span></p></td></tr></tbody></table></div><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Baseline PPV: 56% of all SARS-CoV-2 positive participants were COVID-19-diagnosed inpatients (by HES).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h2>Dates of SARS-CoV-2 tests and hospital spells<o:p></o:p></h2><p class="MsoNormal" style="font-size: medium;">We looked at the effect of insisting that the SARS-CoV-2 test specimen date (<span style="font-family: Courier; font-size: 10pt;">specdate</span>) from SGSS overlaps with the hospital spell (<span style="font-family: Courier; font-size: 10pt;">admidate, disdate</span>) from HES, focusing on comparison 2a/b.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">For <span style="font-family: Courier; font-size: 10pt;">origin==1</span>, the dates did not overlap exactly for 37/557 true COVID-19 inpatients, falling to 4/557 when allowing a ±7 day tolerance. For <span style="font-family: Courier; font-size: 10pt;">reqorg==1</span>, the dates did not overlap exactly for 9/289 true COVID-19 inpatients, falling to 2/289 when allowing a ±7 day tolerance. So the test dates and hospital spell dates were compatible in almost all cases, meaning that the results are not strongly affected by insisting on chronological overlap (with tolerance) or not.</p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><h1>Summary<o:p></o:p></h1><p class="MsoNormal" style="font-size: medium;">The relative performance of the tests behaved as advertised, with <span style="font-family: Courier; font-size: 10pt;">origin==1</span> more sensitive and <span style="font-family: Courier; font-size: 10pt;">reqorg==1</span> more specific (Table 1).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><table border="0" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; color: black; width: 634px;"><tbody><tr style="height: 15.8pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="center" class="MsoNormal" style="text-align: center;"><o:p> </o:p></p></td><td colspan="3" style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 205.95pt;" valign="top" width="275"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 10pt;">origin==1</span><o:p></o:p></p></td><td colspan="3" style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 198.8pt;" valign="top" width="265"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 10pt;">reqorg==1</span><o:p></o:p></p></td></tr><tr style="height: 15.8pt;"><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">%<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">1a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: solid none; border-top-color: windowtext; border-top-width: 1pt; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: solid solid solid none; border-top-color: windowtext; border-top-width: 1pt; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2b<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">1a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2b<o:p></o:p></span></p></td></tr><tr style="height: 15.8pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">Sensitivity<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">80<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">69<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">89<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">45<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">36<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">46<o:p></o:p></span></p></td></tr><tr style="height: 15.8pt;"><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">Specificity<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">47<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">100<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">46<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">88<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">100<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="break-after: avoid; text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">87<o:p></o:p></span></p></td></tr></tbody></table><p class="MsoCaption">Table 1 Sensitivity and specificity of SGSS-derived inpatient indicators<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Table 2 shows baseline PPV (portion of true inpatients in the comparison) against which to compare the PPV and 100%-NPV (respectively, the portions of true inpatients among those flagged and not flagged as inpatients using SGSS). Baseline PPV indicates the enrichment of the baseline population for inpatients.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><table border="0" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; color: black; width: 634px;"><tbody><tr style="height: 15.8pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="center" class="MsoNormal" style="text-align: center;"><o:p> </o:p></p></td><td colspan="3" style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 205.95pt;" valign="top" width="275"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 10pt;">origin==1</span><o:p></o:p></p></td><td colspan="3" style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 198.8pt;" valign="top" width="265"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Courier; font-size: 10pt;">reqorg==1</span><o:p></o:p></p></td></tr><tr style="height: 15.8pt;"><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">%<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">1a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: solid none; border-top-color: windowtext; border-top-width: 1pt; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: solid solid solid none; border-top-color: windowtext; border-top-width: 1pt; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2b<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">1a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2a<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">2b<o:p></o:p></span></p></td></tr><tr style="height: 15.8pt;"><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">Baseline PPV<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">61<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">0.2<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">56<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">61<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">0.2<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">56<o:p></o:p></span></p></td></tr><tr style="height: 15.8pt;"><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">PPV<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">70<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">68<o:p></o:p></span></p></td><td style="border-right-color: windowtext; border-right-width: 1pt; border-style: none solid none none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">68<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">86<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">82<o:p></o:p></span></p></td><td style="border: none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">82<o:p></o:p></span></p></td></tr><tr style="height: 15.8pt;"><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 70.75pt;" valign="top" width="94"><p align="right" class="MsoNormal" style="text-align: right;"><span style="font-family: Helvetica; font-size: 9pt;">100% - NPV<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.65pt;" valign="top" width="89"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">40<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 73pt;" valign="top" width="97"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">0.0<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-right-color: windowtext; border-right-width: 1pt; border-style: none solid solid none; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">24<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">49<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.25pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">0.0<o:p></o:p></span></p></td><td style="border-bottom-color: windowtext; border-bottom-width: 1pt; border-style: none none solid; height: 15.8pt; padding: 0cm 5.4pt; width: 66.3pt;" valign="top" width="88"><p align="center" class="MsoNormal" style="break-after: avoid; text-align: center;"><span style="font-family: Helvetica; font-size: 9pt;">44<o:p></o:p></span></p></td></tr></tbody></table><p class="MsoCaption">Table 2 Positive and negative predictive values of SGSS-derived inpatient indicators<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;">Baseline PPV varied widely depending on the baseline population considered (1a: SARS-CoV-2 tested, 2a: all participants, 2b: SARS-CoV-2 positive) and inpatient definition (1a: any inpatient, 2a/2b: COVID-19-diagnosed inpatients).<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">Directly comparing PPV and 100%-NPV contrasts the trade-off in behaviour between the <span style="font-family: Courier; font-size: 10pt;">origin==1</span> and <span style="font-family: Courier; font-size: 10pt;">reqorg==1 </span>flags. The <span style="font-family: Courier; font-size: 10pt;">origin==1</span> flag <i>wrongly</i> <i>removed</i> true inpatients less often. The <span style="font-family: Courier; font-size: 10pt;">reqorg==1</span> flag <i>wrongly</i> <i>retained</i> false inpatients less often. Thus, the former was better at <i>excluding</i>: it achieved higher 100%-NPV or “false omission rate”. The latter was correspondingly better at <i>including</i>: it achieved higher PPV.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">The<span style="font-family: Courier; font-size: 10pt;"> origin==1</span> flag returned larger numbers of inpatients at the cost of a higher dilution of false inpatients. In all cases, the<span style="font-family: Courier; font-size: 10pt;"> origin==1</span> flag also returned much larger numbers of <i>true</i> inpatients than the <span style="font-family: Courier; font-size: 10pt;">reqorg==1</span> flag. Of course the largest number of true inpatients would be achieved by retaining all participants in the comparison, but the<span style="font-family: Courier; font-size: 10pt;"> origin==1 </span>flag outperformed the baseline PPV in all comparisons.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><br /></p><p class="MsoNormal" style="font-size: medium;">These analyses have some limitations. In particular, not all relevant hospital stays were considered: some were excluded because HES only included finished episodes under the care of a particular consultant. Further, records without discharge dates were excluded, so only spells of continuous stay completed before the censoring date of 31 May 2020 were analysed. A more complete picture will become available in the coming months - until then, the performance metrics presented here are provisional.</p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">The PPV and NPV depend on the baseline population and its proportion of true inpatients. Therefore the metrics calculated apply specifically to the date range 16 March - 30 April. Post April, there were several changes in the tested population. Testing in the community was expanded, although due to technical limitations, only positive test results are currently imported to SGSS from the commercial ‘lighthouse’ laboratories handling this <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/878121/coronavirus-covid-19-testing-strategy.pdf">Pillar 2</a> testing. More importantly from the perspective of identifying participants with more severe COVID-19, inpatient screening for SARS-CoV-2 became routine after April. Therefore it is not reasonable after April to assume that SARS-CoV-2 positive inpatients necessarily showed symptoms of COVID-19, mild or severe, irrespective of how well inpatients were identified using SGSS data.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p><p class="MsoNormal" style="font-size: medium;">By September, HES will cover the majority of the peak epidemic in England, so switching to HES for the identification of COVID-19 is strongly recommended for retrospective analyses. A more difficult question is what to do if a second wave occurs during autumn or winter. There might then be a case for enriching for inpatients using rapidly-available SGSS data. By that time, we would have more data to evaluate the impact of post-April changes to testing on the identification of inpatients using SGSS data to form a better-informed judgement, although the situation is likely to remain dynamic.<o:p></o:p></p><p class="MsoNormal" style="font-size: medium;"><o:p> </o:p></p>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com1tag:blogger.com,1999:blog-5536187228656752547.post-57397251421931912812020-08-13T00:59:00.000-07:002020-08-13T00:59:50.739-07:0026 July COVID-19 PCR test results for UK Biobank<p><span style="font-size: small;"><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;">During June and July further</span><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;"> tranches of COVID-19 PCR test result data for UK Biobank participants, collated from Public Health England data, have been released. The latest data covers the period March 16 - July 26. For details of how to access the data, see </span><a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html" style="color: #4d469c; font-family: arial, tahoma, helvetica, freesans, sans-serif; text-decoration: none;">this post</a><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;">.</span></span></p><ul style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; line-height: 1.4; list-style-image: initial; list-style-position: initial; margin: 0.5em 0px; padding: 0px 2.5em;"><li style="border: none; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"><span style="font-size: small;">1650 participants returned one or more positive tests, of whom 1069 returned tests while a hospital inpatient*</span></span></li><li style="border: none; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"><span style="font-size: small;">11852 participants never returned a positive test, of whom 9325 returned tests while a hospital inpatient</span></span></li></ul><span style="font-size: small;"><span face="" style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;">* This definition of COVID-19 positive inpatient does not require that the positive test and the test while an inpatient necessarily coincide in participants with multiple tests. Requiring them to coincide on the same test reduces this number from 1069 to 1030.</span><br style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;" /></span><div style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;"><span style="font-size: small;"><br /></span></div><span style="font-size: small;"><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;">Compare the totals to the <a href="https://news.bugbank.uk/2020/06/31-may-2020-covid-19-pcr-test-results.html" style="color: #4d469c; text-decoration: none;">31 May 2020 release here</a>.</span><br style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;" /><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;"><br /></span><span face="" style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;"><b>Important updates:</b></span><br style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif;" /></span><ul style="line-height: 1.4; list-style-image: initial; list-style-position: initial; margin: 0.5em 0px; padding: 0px 2.5em;"><li style="border: none; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"><span style="font-size: small;">The number of participants with one or more positive tests increased by 176 since 31 May (a 12% increase), reflecting the lowest infection rates seen since March. While rates remain low, we intend to extract new tranches monthly rather than weekly.</span></span></li><li style="border: none; caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"><span style="font-size: small;">The number of participants with negative but no positive tests increased by 7209 since 31 May (a 155% increase), reflecting increased testing by NHS laboratories.</span></span></li><li style="border: none; caret-color: rgb(68, 68, 68); color: #444444; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;">New negative test results are still absent for some laboratories following the implementation of <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/878121/coronavirus-covid-19-testing-strategy.pdf" style="color: #4d469c; text-decoration: none;">Pillar 2</a> testing, while for other laboratories, the information used to determine evidence of inpatient status (the </span><span style="font-family: courier; font-size: small;">origin</span><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;"> column) is absent for negative test results: see <a href="https://news.bugbank.uk/2020/06/sars-cov-2-negative-inpatient.html">here</a> and mention of 'Respiratory DataMart' in <a href="https://www.microbiologyresearch.org/docserver/fulltext/mgen/6/7/mgen000397.pdf">Armstrong et al (2020)</a> for details.</span></li><li style="border: none; margin: 0px 0px 0.25em; padding: 0.25em 0px;"><span face="" style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;">This latest tranche includes additional data <a href="https://www.microbiologyresearch.org/docserver/fulltext/mgen/6/7/mgen000397.pdf">used to define</a> the </span><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: courier; font-size: small;">origin</span><span face="" style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;"> column (evidence for inpatient status) in the columns </span><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: courier; font-size: small;">acute</span><span face="" style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;"> (the</span><span face="" style="color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;"> ‘Acute Trust’ flag, meaning that the test came from a hospital delivering emergency care), </span><span style="color: #444444; font-family: courier; font-size: small;">hosaq</span><span face="" style="color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: small;"> (the ‘Hospital Acquired Infection’ flag) and reqorg (the Requesting Organization Type associated with the test, which uses <a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=3311">data coding 3311</a>).</span></li></ul><div style="caret-color: rgb(68, 68, 68); color: #444444; font-size: 13px;"><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;">There will be a further post comparing the evidence for inpatient status derived from Public Health England's Second Generation Surveillance System (the </span><span style="font-family: courier;">origin</span><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;">, </span><span style="font-family: courier;">acute</span><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;">, </span><span style="font-family: courier;">hosaq</span><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"> and </span><span style="font-family: courier;">reqorg</span><span face="" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;"> columns) to Hospital Episode Statistics in UK Biobank.</span></div><div style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: 13px;"><br /></div><div style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: 13px;">The long tail of the epidemic in England can be seen in a new version of Figure 4 of <a href="https://www.microbiologyresearch.org/docserver/fulltext/mgen/6/7/mgen000397.pdf" style="font-family: arial, tahoma, helvetica, freesans, sans-serif;">our paper</a> updated to 1 July. For the latest information visit <a href="https://coronavirus.data.gov.uk">coronavirus.data.gov.uk</a>.</div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBUDtETSu7OECzebYw5hD9FhdomzAMrqCPYGXLxReUKUeHwkADEuHAc-CnT9t3Nj2HVMSffhZutCFcG-4kiFFY7gfXp5BVELVAZamxQPbWEwG8I_3HJSB6-xppd28Yjv-iTdFiG42E8J0/s2048/Figure+2020-07-06+143442.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1370" data-original-width="2048" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBUDtETSu7OECzebYw5hD9FhdomzAMrqCPYGXLxReUKUeHwkADEuHAc-CnT9t3Nj2HVMSffhZutCFcG-4kiFFY7gfXp5BVELVAZamxQPbWEwG8I_3HJSB6-xppd28Yjv-iTdFiG42E8J0/s640/Figure+2020-07-06+143442.png" width="640" /></a></div><div style="caret-color: rgb(68, 68, 68); color: #444444; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: 13px;"><br /></div>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com6tag:blogger.com,1999:blog-5536187228656752547.post-3144784196648673492020-06-11T07:30:00.005-07:002020-06-11T07:30:59.759-07:00What happened to the XPNPEP2 signal?The last two releases of COVID-19 test results for the UK Biobank (<a href="https://news.bugbank.uk/2020/05/18-may-2020-covid-19-pcr-test-results.html">18 May</a> and <a href="https://news.bugbank.uk/2020/06/31-may-2020-covid-19-pcr-test-results.html">31 May</a>) have not reproduced the signal of <a href="https://news.bugbank.uk/2020/05/critical-evaluation-of-rs2076205.html">genome-wide significance in XPNPEP2</a>. By contrast, another <a href="https://www.medrxiv.org/content/10.1101/2020.05.31.20114991v1">signal in chromosome 3</a> has meanwhile been detected in an independent cohort and appears to be supported by the COVID-19 Host Genetics Initiative's <a href="https://www.covid19hg.org/results/">May 15th meta-analysis</a>.<br />
<br />
So what is the current status of the signal of association in rs2076205 in XPNPEP2? This signal was unearthed in a comparison of COVID-19 PCR positive versus negative individuals of European ancestry. The rare allele was commoner than expected among PCR negative individuals. Depending how you performed the analysis, the signal was significant or very significant in the UK Biobank cohort. However, there was a difficult-to-explain sensitivity to whether individuals with close relatives in the rest of the cohort were included in the analysis. Even so, I was <a href="https://news.bugbank.uk/2020/05/critical-evaluation-of-rs2076205.html">unable to explain away</a> the signal with measured confounders or population stratification.<br />
<br />
The signal is no longer genome-wide significant in UK Biobank, whether or not you exclude individuals with close relatives. Nor was its significance supported by the <a href="https://www.covid19hg.org/results/">May 15th meta-analysis</a> combining UK Biobank results with other international cohorts, notably <a href="https://www.lifelines.nl/">Lifelines</a>, <a href="https://www.finngen.fi/en">FinnGen</a> and the <a href="https://www.cambridge.org/core/journals/twin-research-and-human-genetics/article/netherlands-twin-register-longitudinal-research-based-on-twin-and-twinfamily-designs/C68488FDD92716CB9ED7C040B9776E2F">Netherlands Twin Register</a>.<br />
<br />
Therefore it is tempting to write off the association as noise in a relatively small sample. Without dismissing that as the possible explanation, here I do a little more digging to try to explain why else there might have been a signal that is now much reduced.<br />
<br />
Perhaps surprisingly, the deviation of allele frequencies from their expectation under the null hypothesis (of no association, as judged against overall allele frequencies among individuals of European ancestry in the Biobank) was driven mainly by PCR negative individuals, rather than PCR positive individuals. PCR negative individuals showed an enrichment for the rare allele. While PCR positive individuals showed a corresponding depletion of the rare allele, the signal was weaker. The trend is still apparent in the data, but its magnitude - and therefore significance - is now reduced.<br />
<br />
The graph shows that the significance of the association generally increased with sample size between mid-March and May 1st, before reversing. Why should that be?<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhG_uOHAMjTmVks11KVyRyEb_AEcxX5PjTu4su2-rq2OPaQrvQsUYC5_xQbe7wrUi197ot0TcSqGoqdAST-e-AsujzHEb2_VEg-5x9TVwTiIlzzz9Yzt2VXja-oniIl6kAJYQuxqby4Mt8/s1600/XPNPEP2-followup.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="358" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhG_uOHAMjTmVks11KVyRyEb_AEcxX5PjTu4su2-rq2OPaQrvQsUYC5_xQbe7wrUi197ot0TcSqGoqdAST-e-AsujzHEb2_VEg-5x9TVwTiIlzzz9Yzt2VXja-oniIl6kAJYQuxqby4Mt8/s640/XPNPEP2-followup.png" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Observed and expected genotype counts and statistical significance of the rare allele at rs2076205 in members of the UK Biobank with European ancestry, classified by SARS-CoV-2 test result: anypos.in (ever tested positive, ever tested while an inpatient), anypos.nin (ever tested positive, never tested while an inpatient), neg.in (never tested positive, ever tested while an inpatient), neg.nin (never tested positive, never tested while an inpatient). Red lines represent analyses including individuals with close relatives in UK Biobank. Blue lines represent analyses excluding individuals with close relatives in UK Biobank. Significance calculated crudely with a binomial test. Expected genotype frequencies calculated from all UK Biobank participants of European ancestry.</td></tr>
</tbody></table>
Given the reliance of the signal on the interpretation of PCR negative individuals, one possible explanation could be a change in inpatient testing at the end of April. The testing criteria before and after the end of April probably differed by hospital, and the date of any change in testing would have varied too, but my clinical colleagues in Oxford have characterized it as follows (and apologies if there are any errors in reproducing the account here):<br />
<br />
<ul>
<li>Before circa 25th April, only individuals deemed likely to have COVID-19 were tested.</li>
<li>From around 25th April onwards, testing of inpatients was drastically broadened.</li>
</ul>
<div>
There is some evidence of an increased rate of testing in the graphs: the allele counts for negative inpatients become steeper around the end of April.</div>
<div>
<br /></div>
<div>
The idea - and this is only an idea - is that PCR negative individuals before 25th April contained a sizeable subgroup of individuals exposed to SARS-CoV-2 who did not present detectable levels of virus, perhaps because they have a degree of resistance to infection. After 25th April, many individuals without true exposure to SARS-CoV-2 were also tested, diluting the signal.</div>
<div>
<br /></div>
<div>
When UK Biobank releases <a href="https://www.ukbiobank.ac.uk/2020/04/covid/">more detailed data on hospital episodes</a>, it may be possible to test this idea, for example by comparing individuals with and without a diagnosis of COVID-19.</div>
<div>
<br /></div>
<div>
There are other possible explanations, including unmeasured confounding, <a href="https://www.medrxiv.org/content/10.1101/2020.05.04.20090506v3">ascertainment bias</a> and noise. The explanation offered above does not explain why the signal in positive inpatients (weaker though it was) also reversed. And there are alternative interpretations of negative inpatients - another clinical colleague of mine has suggested they contain a subgroup of individuals whose disease is more progressed (i.e. worse) at the time of admission, that there may be a window of opportunity early after infection for detecting the virus from throat swabs, and that window was missed in this subgroup.</div>
<div>
<br /></div>
<div>
Whatever the explanation, there is excitement at the discovery of <a href="https://www.medrxiv.org/content/10.1101/2020.05.31.20114991v1">signals elsewhere in the genome</a> by others (which appear to be replicated in independent cohorts including UK Biobank), and the enhanced prospects the discovery represents for finding new ways to tackle the disease.</div>
Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-88873444164817379692020-06-05T13:57:00.003-07:002020-06-06T13:34:47.808-07:0031 May 2020 COVID-19 PCR test results for UK Biobank released<span style="background-color: white; color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: 13px;">The latest tranche of COVID-19 PCR test result data for UK Biobank participants, collated from Public Health England data, has been released. This latest data covers the period March 16 - May 31. For details of how to access the data, see </span><a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html" style="color: #4d469c; font-family: arial, tahoma, helvetica, freesans, sans-serif; font-size: 13px; text-decoration: none;">this post</a><span style="background-color: white; color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: 13px;">.</span><br />
<ul>
<li><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">1474 returned one or more positive tests, of whom 991 returned tests while a hospital inpatient*</span></li>
<li><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">4643 never returned a positive test, of whom 3457 returned tests while a hospital inpatient</span></li>
</ul>
<span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">* This definition of COVID-19 positive inpatient does not require that the positive test and the test while an inpatient necessarily coincide in participants with multiple tests. Requiring them to coincide on the same test reduces this number from 991 to 976.</span><br />
<div>
<br /></div>
<span style="background-color: white; color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: 13px;">Compare the totals to the <a href="https://news.bugbank.uk/2020/05/18-may-2020-covid-19-pcr-test-results.html">18 May 2020 release here</a>.</span><br />
<span style="background-color: white; color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: 13px;"><br /></span><span style="background-color: white; color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: 13px;"><b>Important notes regarding negative test results:</b></span><br />
<ul>
<li><span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">Public Health England has restructured its databases to manage large scale testing in response to implementation of the <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/878121/coronavirus-covid-19-testing-strategy.pdf">UK Government strategy's Pillar 2</a>.</span></li>
<li><span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">Consequently, <u>new negative test results are absent for some laboratories</u> from this release. </span><span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;">We aim to incorporate the omitted test results in future releases.</span></li>
</ul>
<div>
<span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);"><b>Changes to download mechanism:</b></span></span></div>
<div>
<span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);"><br /></span></span></div>
<div>
<span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);">UK Biobank have slightly changed the method for downloading the covid19_result table. I have <a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html">updated the steps here</a>.</span></span><br />
<span style="color: #444444; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);"><br /></span></span>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivDJIaz5wgeBL0wGO7exaMX3cbM9TSoPwfZu0jCpCUJ1GzVSUp7SeymUnl13hqNNJtI4yv8Fk5BkYxIX2ym7-HeHXVQyqlyfF24P4OJMZk8Q5v1qU-RCiL7LhfolUq_bcLt5CAa8Rc1io/s1600/fig5_0601.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1071" data-original-width="1600" height="432" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivDJIaz5wgeBL0wGO7exaMX3cbM9TSoPwfZu0jCpCUJ1GzVSUp7SeymUnl13hqNNJtI4yv8Fk5BkYxIX2ym7-HeHXVQyqlyfF24P4OJMZk8Q5v1qU-RCiL7LhfolUq_bcLt5CAa8Rc1io/s640/fig5_0601.png" width="640" /></a></div>
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Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-16470082371861907752020-06-01T07:02:00.001-07:002020-06-01T07:11:18.589-07:00SARS-CoV-2 negative inpatient identification issueInternal data quality checks have highlighted an issue with the identification of inpatient versus non-inpatient status among SARS-CoV-2 <b>negative</b> test results at some laboratories. This issue affects the PCR-based tests that we have linked to UK Biobank from Public Health England (field <a href="https://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=40100">40100</a>).<br />
<br />
<b>For some laboratories, we report SARS-CoV-2 negative inpatients as non-inpatients (value 0 in the <i><a href="https://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=40100">origin</a></i> column).</b><br />
<br />
The issue became apparent because we report large numbers of negative test results for some laboratories, none (or a very small number) of which are identified as inpatients. Notable laboratories include<br />
<br />
<ul>
<li>Northern General Hospital (Sheffield)</li>
<li>St George’s Hospital Tooting</li>
<li>Leeds General Infirmary</li>
<li>Oxford John Radcliffe</li>
<li>Darent Valley Hospital Dartford</li>
<li>Royal Liverpool University Hospital</li>
</ul>
<div>
Additionally, we appear to have intermittently reported COVID-19 negative inpatients as non-inpatients for Sunderland Royal Infirmary. The identity of the laboratory is coded in the <i><a href="https://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=40100">laboratory</a></i> column. UK Biobank <a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=1856">codes</a> these seven laboratories as 38, 11, 31, 40, 19, 56 and 63 respectively.</div>
<div>
<br /></div>
<div>
We have tracked down the source of the issue to heterogeneity in the processing of negative results between laboratories. All laboratories report positive results to the Second Generation Surveillance System (SGSS). Usually only positive microbiological results are reported to SGSS. Exceptionally for SARS-CoV-2, negative results are also reported. This happens in two ways:</div>
<div>
<ol>
<li>Directly to SGSS, with a pseudo-code indicating the organism (SARS-CoV-2) and test result (negative), where usually an organism alone is reported. Most laboratories have taken this approach.</li>
<li>Directly to Respiratory DataMart, a system set up to monitor influenza. The affected laboratories have taken this approach. We access the negative results for these laboratories separately, and do not import data required to identify inpatient status.</li>
</ol>
<div>
We are investigating a remedy for the issue. Meanwhile we advise researchers to be aware of the potential for artefacts, for example when comparing positive inpatients to negative inpatients.</div>
</div>
<div>
<br /></div>
<div>
(Strictly speaking, the <a href="https://biobank.ndph.ox.ac.uk/showcase/coding.cgi?id=1855">coding in UK Biobank</a> is correct:</div>
<div>
<div>
<ul>
<li>0: No explicit evidence in microbiological record that the participant was an inpatient</li>
<li>1: Evidence from microbiological record that the participant was an inpatient</li>
</ul>
</div>
</div>
<div>
So the issue is one of heterogeneity of evidence, which the careful wording allows for.)</div>
<div>
<br /></div>
Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-74953553842107844862020-05-26T05:27:00.000-07:002020-05-26T05:27:07.299-07:0018 May 2020 COVID-19 PCR test results for UK Biobank released<span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;">The latest tranche of COVID-19 PCR test result data for UK Biobank participants, collated from Public Health England data, has been released. This latest data covers the period March 16 - May 18. For details of how to access the data, see </span><a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html" style="color: #4d469c; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px; text-decoration: none;">this post</a><span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;">.</span><br />
<br />
<ul>
<li><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;">1326 returned one or more positive tests, of whom 932 returned tests while a hospital inpatient*</span></li>
<li><span style="caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;">3184 never returned a positive test, of whom 2254 returned tests while a hospital inpatient</span></li>
</ul>
<br />
<span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;"><span style="background-color: white; caret-color: rgb(68, 68, 68);"></span></span><br />
<span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);">* This definition of COVID-19 positive inpatient does not require that the positive test and the test while an inpatient necessarily coincide in participants with multiple tests. Requiring them to coincide on the same test reduces this number from 932 to 921.</span></span><br />
<div>
<br /></div>
<span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;">Compare the totals to the <a href="https://news.bugbank.uk/2020/05/latest-covid-19-pcr-test-results-for-uk.html">3 May 2929 release here</a>.</span><br />
<span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;"><br /></span>
<span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;"><b>Important notes regarding negative test results:</b></span><br />
<br />
<ul>
<li><span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);">Public Health England has restructured its databases to manage large scale testing in response to implementation of the <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/878121/coronavirus-covid-19-testing-strategy.pdf">UK Government strategy's Pillar 2</a>.</span></span></li>
<li><span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;">Consequently, <u>new negative test results are absent for some laboratories</u> from this release. </span><span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;">We aim to incorporate the omitted test results in future releases.</span></li>
</ul>
<span style="background-color: white; caret-color: rgb(68, 68, 68); color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px;"><br /></span>
<span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);">Here is a new version of Figure 4 of <a href="https://news.bugbank.uk/2020/04/updated-preprint-linking-covid-19-tests.html">our paper</a>, updated to reflect this latest tranche of test results. For a daily updating summary of lab-confirmed cases in England, visit <a href="http://coronavirus.data.gov.uk/">coronavirus.data.gov.uk</a>.</span></span><br />
<div style="text-align: center;">
<span style="color: #444444; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-small;"><span style="caret-color: rgb(68, 68, 68);"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhVC-di_B_R6zL4a2inZ5rOGeaAsW2i0yuK3dV1G3PGedOMC1uW40NTW8vlrscYqby20T4-Nm-A2ljNz19LwbXSVv5qZi516yCdG3LS1sZCdA6c-B9SG8r6ElzWzr5fA8LRdVFZvwGE8vA/s1600/fig4_0519.png" imageanchor="1"><img border="0" height="433" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhVC-di_B_R6zL4a2inZ5rOGeaAsW2i0yuK3dV1G3PGedOMC1uW40NTW8vlrscYqby20T4-Nm-A2ljNz19LwbXSVv5qZi516yCdG3LS1sZCdA6c-B9SG8r6ElzWzr5fA8LRdVFZvwGE8vA/s640/fig4_0519.png" width="640" /></a></span></span></div>
Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com2tag:blogger.com,1999:blog-5536187228656752547.post-47078642378114478012020-05-13T03:57:00.002-07:002020-05-13T05:03:07.919-07:00Critical evaluation of the rs2076205 association with COVID-19 susceptibility in UK BiobankIn this post I critically evaluate the evidence for an association between rs2076205 and COVID-19 susceptibility, as previously reported <a href="https://news.bugbank.uk/2020/04/suggestive-hits-for-covid-19-positive.html">here</a>, <a href="https://news.bugbank.uk/2020/05/xpnpep2-is-genome-wide-significant-in.html">here</a> and <a href="https://news.bugbank.uk/2020/05/quasi-replication-of-covid-19.html">here</a>. There is a need to take stock because the sample sizes are as yet modest, and small differences in the details of the analysis of the UK Biobank data appear to produce different interpretations of the strength of evidence.<br />
<br />
Statistical considerations that question the association include the observations that:<br />
<ul>
<li>The significance of the association goes down if individuals with close relatives in UK Biobank are included in the analysis.</li>
<li>The signal appears specific to UK Biobank participants of white European ancestry.</li>
<li>Power to detect a true association at a <i>particular</i> variant, if one were to exist, would be low because the sample size is modest.</li>
</ul>
Statistical considerations that support the association include the observations that:<br />
<ul>
<li>The direction and magnitude of the effect are compatible whether individuals with close relatives in UK Biobank are included in the analysis or not.</li>
<li>The direction and magnitude of effect are compatible when comparing COVID-19 +ve individuals to either (i) COVID-19 -ve individuals, as in the discovery analysis, and (ii) untested individuals, as in the quasi-replication analysis.</li>
<li>In individuals of white European ancestry, the variant is not strongly stratified geographically nor does it appear confounded with any of a large number of variables recorded by UK Biobank.</li>
</ul>
<h4>
Robustness to the inclusion of close relatives</h4>
<div>
Comparison of results to other groups in the <a href="https://www.covid19hg.org/">COVID-19 Host Genetics Initiative</a> revealed that the signal in XPNPEP2 varies depending on the details of the analysis. <a href="https://www.mcgill.ca/genepi/people-0">Tomoko Nakanishi and Brent Richards</a> have been helpful picking this apart. The differences are driven by whether one excludes participants with other close relatives (cousins or closer) in the analysis (as I do) or not (as many others do).</div>
<div>
<br /></div>
<div>
The table compares the effect of the minor (rarer) allele on the risk of a PCR positive for COVID-19, the standard error (uncertainty), and the -log<sub>10</sub> <i>p</i>-value (bigger is more statistically interesting) in a logistic regression analysis controlling for sex, age, age*age, sex*age and 40 genetic principal components:</div>
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt1iufR-g2dxomA-iYBTy9CWOAW33hGIb87t76NhVj852Tr1SWKDMn3Zui4bsYefUT9D5joUp9icSPSHAJG2ij5K7n0B82S_4jk_dnGqWT1aPwRTFvs7aJ4qR_YOF6S3jO0rVwdMYqdkc/s1600/relanal.png" imageanchor="1"><img border="0" height="55" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt1iufR-g2dxomA-iYBTy9CWOAW33hGIb87t76NhVj852Tr1SWKDMn3Zui4bsYefUT9D5joUp9icSPSHAJG2ij5K7n0B82S_4jk_dnGqWT1aPwRTFvs7aJ4qR_YOF6S3jO0rVwdMYqdkc/s400/relanal.png" width="400" /></a></div>
<div>
<br />
The reasons for including individuals with close relatives in UKB are:<br />
<ul>
<li>Increased sample size should reduce uncertainty and improve the ability to discover signals.</li>
<li>There are no pairs of close relatives who have both received a PCR test result among English UKB participants, so far.</li>
</ul>
<div>
The reasons for excluding individuals with close relatives in UKB are:</div>
<ul>
<li>Pairs of close relatives may appear in the PCR test positive vs negative comparison in future and do currently feature in other comparisons (e.g. PCR test positive vs no test).</li>
<li>Determining inclusion/exclusion criteria depending on outcome variables (e.g. do they currently have a PCR test result) potentially introduces undesired ascertainment effects.</li>
<li>Close relatives are more likely to share exposure to unmeasured environmental risk factors, notably exposure to SARS-CoV-2 which is highly variable and prerequisite for disease. If this non-independence is not fully controlled (difficult even with sophisticated tools) the inclusion of outcomes among a group of genetically similar individuals can unduly influence results.</li>
</ul>
<div>
On balance one would think excluding close relatives is the cautious approach, but with modest sample sizes the argument that more is better has merit. What is unusual is that including more individuals reduces signal at this gene.</div>
<div>
<h4>
Signal in other ancestries</h4>
<div>
</div>
</div>
<div>
The signal at SNP rs2076205 in XPNPEP2 is not apparent in UKB participants of non-white European ancestry. This means that it does not appear to be able to account for the <a href="https://www.bbc.co.uk/news/health-52602467">strong increased risk</a> of COVID-19 among individuals of non-white European ancestry in England.</div>
<div>
<br /></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhUqwD838nyNsLMPk0Rts5JAbl7UJih4EIDW2WjLxYi_RTibV5ZdPapIoJ77UiNmMKX-N-arRX1s74u4oc9oxGZ5044CYXWnX-QydoUddxvpIYfE4WPyeXeVktXZaP8cPC47qA45w03zfU/s1600/ancanal.png" imageanchor="1"><img border="0" height="55" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhUqwD838nyNsLMPk0Rts5JAbl7UJih4EIDW2WjLxYi_RTibV5ZdPapIoJ77UiNmMKX-N-arRX1s74u4oc9oxGZ5044CYXWnX-QydoUddxvpIYfE4WPyeXeVktXZaP8cPC47qA45w03zfU/s400/ancanal.png" width="400" /></a></div>
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</div>
<h4>
Geographical stratification</h4>
<div>
In considering whether the signal could be an artefact, it is important to look at geographical stratification of the allele because risk factors including exposure to SARS-CoV-2 vary geographically. The figure shows the frequency of the minor allele across England, which was the allele estimated to be protective, among those of white European ancestry only. The map suggests that the allele has broadly similar frequency across England, although there are some local pockets of higher allele frequency scattered around. The map does not show a geographical trend (for example increasing allele frequency moving from North to South). (<i>Note the density of points reflects UKB's sampling distribution, which was focused on particular urban centres.</i>)<br />
<br /></div>
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-D-RDyVM6c8dwITBkx2QxJQxea-m-bcuhnX-moZveoho5LMOr1M7YHUxhxBhP1iTXZaHglUtMjDsnFYx0_hNjlunQDIHB92r856m9dA-FxNX5kZDtT0S1AhSnaV0y5V19bBIzcAmPxSk/s1600/rs2076205.geography.key.png" imageanchor="1"><img border="0" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-D-RDyVM6c8dwITBkx2QxJQxea-m-bcuhnX-moZveoho5LMOr1M7YHUxhxBhP1iTXZaHglUtMjDsnFYx0_hNjlunQDIHB92r856m9dA-FxNX5kZDtT0S1AhSnaV0y5V19bBIzcAmPxSk/s400/rs2076205.geography.key.png" width="400" /></a></div>
<div>
<h4>
Robustness to measured confounders</h4>
Supposing rs2076205 had no effect on susceptibility to COVID-19, then what other explanations are there for the strong signal of association? To address this question <a href="https://www.bdi.ox.ac.uk/Team/nicolas-arning">Nicolas Arning</a> and I have investigated the large number of variables recorded in UKB. In particular, Nick has helped to sift through the variables by applying machine learning methods, mainly <a href="https://en.wikipedia.org/wiki/XGBoost">XGBoost</a>.<br />
<br />
In the table, we have investigated the effect of including potential confounders on the association between COVID-19 PCR positive vs negative, both in terms of the statistical significance (measured by the -log<sub>10</sub> <i>p</i>-value) and the direction and magnitude of the effect itself. The focus is on individuals of white European ancestry, since that was where the signal was found.<br />
<br />
The short story is we have failed to make the signal go away by including any of a large number of covariates. Moreover, the direction and magnitude of the effect is remarkably consistent, indicating that rs2076205 is not very correlated with any of the >18,000 covariates available. We have included potential confounders directly in the logistic regression, including those we might expect to be important beforehand (geographical location, genotyping array), known risk factors (body mass index), variables that came out in early analyses (Townsend deprivation index) and variables suggested by the XGBoost analysis. We have also directly included composite predictors produced by XGBoost.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEigs07pTMMbkwIO4hkvtO1bGmhA_bfKCAWQd-zEJX8_un_2UJvSAsgaYGfjCXFrBEzKGJHo0J6tnbFE_bD6XPrxxnvezJ-uY6mmdCxny3JZoIppaA3LSSDRZruff6_Tmvbe2HmH9B8KIs8/s1600/confounderanalysis.png" imageanchor="1"><img border="0" height="331" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEigs07pTMMbkwIO4hkvtO1bGmhA_bfKCAWQd-zEJX8_un_2UJvSAsgaYGfjCXFrBEzKGJHo0J6tnbFE_bD6XPrxxnvezJ-uY6mmdCxny3JZoIppaA3LSSDRZruff6_Tmvbe2HmH9B8KIs8/s400/confounderanalysis.png" width="400" /></a></div>
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<div>
<h4>
Analysis of individuals with close relatives in UK Biobank</h4>
We investigated why inclusion or exclusion of individuals with close relatives in UK Biobank affects the signal, building on an earlier <a href="https://news.bugbank.uk/2020/05/quasi-replication-of-covid-19.html">subgroup analysis</a>.<br />
<br />
Individuals with other close relatives in UK Biobank are not a random subset of all UKB participants. They are stratified geographically, because they are more likely to be found in the most densely-sampled urban areas and they differ in other respects. Nick ran an XGBoost analysis to identify predictors of having a close relative in UKB. Prediction had a low specificity and sensitivity of roughly 60%. Nonetheless, the predictors with highest feature importance were:<br />
<ul>
<li>Number of full brothers (UKB code 1873)</li>
<li>Number of full sisters (1883)</li>
<li>Distance Euclidean to coast (24508)</li>
<li>Time urine sample collected (20035)</li>
<li>Country of birth UK elsewhere (1647)</li>
<li>Length of time at current address (699)</li>
<li>Frequency of friend family visits (1031)</li>
</ul>
<div>
I included Nick's XGBoost predictor of having UKB relatives in the logistic regression (see table above) but the predictor did not alter the signal of association at rs2076205, whether relatives were excluded (as shown) or not.</div>
<br />
The take-home is we don't understand why actually including versus excluding relatives in UKB affects the signal of association, but given the lack of evidence for stratification and confounding of rs2076205, it may be a combination of (i) re-weighting the contribution to the analysis of different regions or test centres and (ii) differences in interpretation or ascertainment of the PCR positive-versus-negative outcome by region or test centre. The latter I have tried to investigate by subgroup analysis but the numbers are as yet too small.<br />
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<h4>
Statistical evaluation of the signal of association at rs2076205</h4>
Here I summarize the statistical evidence favouring or disfavouring an association between rs2076205 and susceptibility to COVID-19. The figure shows the relative strength of evidence for the association (positive and bigger is stronger) as a function of the effect size in four logistic regression models (discovery vs quasi-replication, excluding vs including relatives) and two combined models (excluding vs including relatives). The idea is that one can weight the strength of evidence by one's prior expectation of observing an effect of a given magnitude in a common SNP (~25% frequency). To assist, known effect sizes discovered in other genome-wide association studies for susceptibility to infection are marked from <a href="https://www.nature.com/articles/s41467-017-00257-5">Tian and colleagues (2017)</a>.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgOfPRYyIPYv4oesN6m7cZzlw8Y22UB44BmDPzqPRVqVIUbe3d3HyZos1MSLKVv4BZs0aA60T5U20tQTWXd5b1ZYUVxEBy8aw1Lj_puqu-OGAfZPqJ3ozDtiKwEw1KTabXfsikQuRYF8po/s1600/Rplot.png" imageanchor="1"><img border="0" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgOfPRYyIPYv4oesN6m7cZzlw8Y22UB44BmDPzqPRVqVIUbe3d3HyZos1MSLKVv4BZs0aA60T5U20tQTWXd5b1ZYUVxEBy8aw1Lj_puqu-OGAfZPqJ3ozDtiKwEw1KTabXfsikQuRYF8po/s400/Rplot.png" width="400" /></a></div>
Briefly, the result of combining evidence across the <a href="https://news.bugbank.uk/2020/05/xpnpep2-is-genome-wide-significant-in.html">discovery</a> and <a href="https://news.bugbank.uk/2020/05/quasi-replication-of-covid-19.html">quasi-replication</a> analyses indicates that<br />
<ul>
<li>The statistical evidence for an association between rs2076205 and susceptibility to COVID-19 just meets the stringent criterion for 'genome-wide' significance if one includes close relatives (orange line).</li>
<li>The evidence substantially surpasses the 'genome-wide' significance criterion if one excludes close relatives (red line).</li>
<li>The effect size of the SNP is broadly similar whether one excludes or includes relatives, and between discovery and quasi-replication analyses.</li>
<li>The effect size is not outlandishly large compared to previous studies of infection.</li>
</ul>
<br />
In more detail, the <i>y</i>-axis shows the log<sub>10</sub> likelihood ratio between the alternative hypothesis with the stated effect size and the null hypothesis with effect size zero. The log-likelihoods are maximized with respect to all other parameters, so they have the same degrees of freedom, making the log-likelihoods <a href="https://en.wikipedia.org/wiki/Neyman%E2%80%93Pearson_lemma">directly comparable</a>. The log-likelihood is essentially acting as a <a href="https://en.wikipedia.org/wiki/Bayes_factor">Bayes factor</a> between the alternative and null hypotheses.<br />
<br />
If one were testing a single candidate SNP, <a href="https://en.wikipedia.org/wiki/Bayes_factor#Interpretation">Jeffreys' interpretation</a> of the <i>y</i>-axis would mean above 0.5 represents substantial evidence in favour of the association. However, there are generally considered around 10<sup>6</sup> effective tests in a genome-wide association study, so the threshold becomes 6.5. This is equivalent to the 'genome-wide' significance threshold for <i>p</i>-values of 5×10<sup>-8</sup>, indicated on the figure after transforming to the log-likelihood scale.<br />
<br />
Since the logistic regression is not quite identical to the SAIGE analysis, which is preferred because of a more sophisticated model of genetic covariance, I have indicated with stars the maximized likelihood and corresponding effect size estimate from SAIGE. The values at the grey and blue stars (analyses including relatives) were provided by <a href="https://www.mcgill.ca/genepi/people-0">Tomoko Nakanishi</a>.<br />
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<h4>
Biological considerations</h4>
<a href="https://news.bugbank.uk/2020/05/xpnpep2-is-genome-wide-significant-in.html">As discussed previously</a>, XPNPEP2 appears to be a very plausible candidate for a role in susceptibility to COVID-19. It belongs to a pathway in common with ACE2, the receptor by which SARS-CoV-2 gains entry to the cell. Moreover, its involvement in <a href="https://en.wikipedia.org/wiki/Bradykinin">bradykinin</a> signalling and its <a href="https://www.omim.org/entry/300145">previous implication in angioedema</a> lends support to a new and - from the perspective of treatment options - potentially important hypothesis that the <a href="https://en.wikipedia.org/wiki/Kinin%E2%80%93kallikrein_system">kallikrein-kinin system</a>, rather than the <a href="https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system">renin-angiotensin (RAS) system</a>, may mediate the life-threatening pathophysiology of COVID-19:<br />
<br />
<b><a href="https://elifesciences.org/articles/57555">Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome</a></b><br />
F. L. van de Veerdonk, M. G. Netea, M. van Deuren, J. W. M van der Meer, Q. de Mast, R. J. Brüggemann and H. van der Hoeven (2020)<br />
<i>eLife</i> <b>9</b>: e57555<br />
<br />
<h4>
Conclusions</h4>
In summary, the statistical genetic evidence from the UK Biobank cohort is 'substantial' or 'decisive' depending on whether one includes or excludes close relatives, but the signal appears restricted to those of white European ancestry. The >1000-fold difference in strength of evidence is a concern for the robustness of the association. Yet detailed analyses of the SNP in question do not reveal stratification or confounding. The phenomenon may therefore reflect differences in the interpretation or ascertainment of the COVID-19 PCR positive and negative outcomes by region or testing centre. There is a desire to replicate the signal in an independent population, taking care to consider the potential for COVID-19 test results and take-up to vary from place-to-place. There is a need to urgently find improved interventions for the ongoing pandemic, and the analyses here lend support to the kallikrein-kinin blockade hypothesis.<br />
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Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-47144431081178669792020-05-08T09:06:00.003-07:002020-05-08T09:06:52.409-07:00Quasi-replication of a COVID-19 susceptibility locus in UK BiobankTo gain broad acceptance that a genetic variant is truly associated with a trait requires (i) a strong signal in the population in which it was discovered, after controlling for possible artefacts and (ii) a replication of the signal and direction of effect in an independent population.<br />
<br />
Quasi-replication is a weaker form of replication in which a related trait in the same population is used in step (ii), instead of the same trait in an independent population: see e.g. <a href="https://www.nature.com/articles/ng.3552?proof=trueIn%252525EF%252525BB%252525BF">this paper</a>. The assumption is that genetic variant affects both traits in the same way.<br />
<br />
Quasi-replication supports the association between <a href="https://news.bugbank.uk/2020/05/xpnpep2-is-genome-wide-significant-in.html">COVID-19 susceptibility and rs2076205 in XPNPEP2</a>, a signal that already meets the step (i) condition. The related traits I have studied are<br />
<br />
<ul>
<li>Step 1 (discovery): Susceptibility to COVID-19. Specifically, whether individuals in UK Biobank that were tested for SARS-CoV-2 were positive (cases) or negative (controls).</li>
<li>Step 2 (quasi-replication): Susceptibility to severe COVID-19. Specifically, comparing UK Biobank participants positive for SARS-CoV-2 and requiring hospitalization (cases), versus UK Biobank participants not tested for SARS-CoV-2 (controls).</li>
</ul>
<div>
These definitions require some justification. The step 1 trait better controls for who has been exposed to SARS-CoV-2, but it does not differentiate infection severity. The step 2 trait does not control for whether people have been exposed to SARS-CoV-2, but it defines severity as COVID-19 requiring hospitalization. The untested population is a reasonable control here because a minority of infected people would require hospitalization if they were infected. The cases partially overlap between trait definitions, but the controls do not, so the tests are independent if the variant has no effect and artefacts are avoided.</div>
<h4>
The rs2076205 variant quasi-replicates in UK Biobank</h4>
<div>
To test whether the most significant variant in step 1 quasi-replicated, I used the <a href="https://news.bugbank.uk/2020/05/xpnpep2-is-genome-wide-significant-in.html">sub-group analysis</a> to predict the direction of effect and identify the subgroup in which the effect would most likely be strongest. This led to the specific hypothesis that</div>
<blockquote class="tr_bq">
<i>The rare allele at rs2076205 reduces the risk of COVID-19 requiring hospitalization among the white European subgroup of men and women, in an analysis that excludes close relatives.</i></blockquote>
<div style="text-align: left;">
In a replication study, the requirement for deeming a result statistically interesting is usually considered to be much less stringent. In this case, it could be argued that the single-tailed test would require a <i>p</i>-value of 0.01 or smaller. </div>
<div style="text-align: left;">
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<div style="text-align: left;">
This reduced stringency is convenient because the inability to know who has been exposed to SARS-CoV-2 probably makes the step 2 trait noisy, which hurts statistical power.</div>
<div style="text-align: left;">
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<div style="text-align: left;">
The result is that rs2076205 does quasi-replicate, with a one-tailed <i>p</i>-value of 0.00012, an estimated effect size of -0.21 and 95% confidence interval of (-0.33, -0.10). The estimated effect size is a log odds ratio, and implies that a male with a copy of the rare allele is 19% less likely to experience COVID-19 severe enough to require hospitalization, compared to a male with a copy of the common allele.</div>
<div style="text-align: left;">
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<div style="text-align: left;">
The Manhattan plots, with the XPNPEP2 gene marked, are shown, first for step 1 (discovery):</div>
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLP5HXA77Hn4qLLHsLTSJDbji3slJXPvVYgid1GIiWVuQO6I3uW3-Y2rXV5PcSEm6WzowiCHIt5VKeKvTQ-xWoWUlKGoa56iOvzZ7wGESQRDu_VKkfDV5ARSev5_AOgz1ryI6nPUnPLr4/s1600/XPNPEP2ANA5.png" imageanchor="1"><img border="0" height="384" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLP5HXA77Hn4qLLHsLTSJDbji3slJXPvVYgid1GIiWVuQO6I3uW3-Y2rXV5PcSEm6WzowiCHIt5VKeKvTQ-xWoWUlKGoa56iOvzZ7wGESQRDu_VKkfDV5ARSev5_AOgz1ryI6nPUnPLr4/s640/XPNPEP2ANA5.png" width="640" /></a></div>
<div style="text-align: left;">
And then for step 2 (quasi-replication):</div>
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEha1in-IXCCjlCZgWI2XzkWSU6EUT_TaIbzTSLBZBN__8ipza-NdReJHV_Z6df-EamJ15JKDQnsuuKavYKHVRIAXTf0YFr_MRTN24M7wff-pdwjwWhGeCVzUkrUxlfY-SVbYU8-NYNHTVQ/s1600/XPNPEP2ANA6.png" imageanchor="1"><img border="0" height="384" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEha1in-IXCCjlCZgWI2XzkWSU6EUT_TaIbzTSLBZBN__8ipza-NdReJHV_Z6df-EamJ15JKDQnsuuKavYKHVRIAXTf0YFr_MRTN24M7wff-pdwjwWhGeCVzUkrUxlfY-SVbYU8-NYNHTVQ/s640/XPNPEP2ANA6.png" width="640" /></a></div>
<div style="text-align: left;">
The Manhattan plots show that the signal is centred on the XPNPEP2 gene in both discovery and quasi-replication subjects. More work would be needed to dissect the signal, determine whether it is one signal or multiple, and identify the possible genetic mechanism, particularly as rs2076205 occurs in an intron.</div>
<h4>
Subgroup analysis</h4>
<div style="text-align: left;">
Having testing the specific quasi-replication hypothesis, I repeated the analysis to understand whether the effect differs in different subgroups.</div>
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhTiZRLBnmQu6HgtTvBR01anZW3RF9lZqdz8Vd8gMxQbMcai6rDZkkv-2Nl6V9aT_-YBoxiWPcR2XYV_MQYO7dbVUwGjaIiQMhZA3UsWNZdFEz9hmSxZNBrUIb2cPRFI0W0RxIqXvbSOcM/s1600/forest-qr.png" imageanchor="1"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhTiZRLBnmQu6HgtTvBR01anZW3RF9lZqdz8Vd8gMxQbMcai6rDZkkv-2Nl6V9aT_-YBoxiWPcR2XYV_MQYO7dbVUwGjaIiQMhZA3UsWNZdFEz9hmSxZNBrUIb2cPRFI0W0RxIqXvbSOcM/s640/forest-qr.png" width="320" /></a></div>
<div style="text-align: left;">
Like in step 1 (discovery), the effect appears slightly stronger in males than females, and in genetically-identified white Europeans compared to other groupings. The signal is again diluted by failing to exclude close relatives, whose inclusion can affect analyses in unexpected ways. The specific analysis used for quasi-replication is marked with a red asterisk.</div>
<div style="text-align: left;">
<br /></div>
<div style="text-align: left;">
The SAIGE output for the quasi-replication analysis was:</div>
<div style="text-align: left;">
<span style="font-family: Courier New, Courier, monospace; font-size: x-small;">CHR POS rsid SNPID Allele1 Allele2 AC_Allele2 AF_Allele2 imputationInfo N BETA SE Tstat p.value p.value.NA Is.SPA.converge varT varTstar AF.Cases AF.Controls</span></div>
<div style="text-align: left;">
<div>
<span style="font-family: Courier New, Courier, monospace; font-size: x-small;">X 128893417 rs2076205 X:128893417_C_T C T 153134.094117643 0.270302781358809 0.990731443602318 283264 -0.212939151738995 0.0578228858969803 -64.2609437640745 0.000230857982728242 0.000216327322582023 1 301.780782159031 303.712925876132 0.205153495741731 0.270416828147468</span></div>
<div>
The analysis included age, sex, age*age, age*sex and 20 genetic principal components.</div>
<div>
<br /></div>
<div>
There are some potential criticisms of the analysis, beyond using the same population to validate the association. In particular, the step 2 analysis is itself of direct interest, and having run a genome-wide association study (GWAS) and found nothing significant, is it reasonable to claim that a single constituent result from that GWAS provides quasi-replication of a separate GWAS? I would argue that falsifiability was possible: the effect could have been in the opposite direction and the signal strength could have been below that required for replication. Since there were two opportunities for falsification, the quasi-analysis does provide additional support that XPNPEP2 is a COVID-19 susceptibility locus.</div>
<div>
<br /></div>
<div>
<br /></div>
</div>
Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-27230880341630262602020-05-07T07:35:00.004-07:002020-05-08T06:25:17.491-07:00XPNPEP2 is genome-wide significant in a COVID-19 +ve/-ve analysis of UK Biobank participantsOn April 19 I wrote about a <a href="https://news.bugbank.uk/2020/04/suggestive-hits-for-covid-19-positive.html">biologically interesting signal in XPNPEP2</a> in a comparison of COVID-19 positive and negative individuals who have participated in UK Biobank. In the <a href="https://news.bugbank.uk/2020/05/latest-covid-19-pcr-test-results-for-uk.html">latest data release</a>, which represents a doubling in sample size for this analysis, the hit is genome-wide significant in an analysis of white Europeans. However, it is not genome-wide significant when analysing individuals with all ancestries.<br />
<br />
The top hit is <a href="https://genome-euro.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chrX%3A128893317%2D128893517&hgsid=238205903_X2ZPs17assWg3GIrAqmeZivAHCiu">rs2076205</a>, a single nucleotide polymorphism whose common allele occurs in 68% of COVID-19 negative individuals and 79% of COVID-19 positive individuals. It has a <i>p</i>-value of 1.1 in 10 million, which is below the widely-used threshold of 5 in 10 million that is often deemed statistically interesting.<br />
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgzIURflhUBfcGrMdSZ-n1-fmTVhGdBnyCruOCpjajOkkOIsmIc7XDv-Ef9lSVIxS9xHDRs52ODBsdVNSPBVTbUBZeAG-290QTsZ1vzSosli6_1AscayW039n9KVGvW6FVbqiHKPyRWWcI/s1600/posneg-eur.png" imageanchor="1"><img border="0" height="384" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgzIURflhUBfcGrMdSZ-n1-fmTVhGdBnyCruOCpjajOkkOIsmIc7XDv-Ef9lSVIxS9xHDRs52ODBsdVNSPBVTbUBZeAG-290QTsZ1vzSosli6_1AscayW039n9KVGvW6FVbqiHKPyRWWcI/s640/posneg-eur.png" width="640" /></a></div>
<br />
In the analysis of individuals of all ancestries, the signal is substantially muted, and no variants are genome-wide significant. The reasons for the difference in analysis are still unclear, but the SNP does appear to be strongly population stratified.<br />
<div style="text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhszcm1iy_0pXOkEuu20SSWuWAk7fVUzdXvBQQyCKdtZ5RYdqeA-ZsuIoGWdcX5LCmo94MmcEk79zK5EsteyffX5slWXDhV8RjySJgd6omY5zw0r9scD67YII_24HIZO49Bei5bZDzzxKg/s1600/posneg-any.png" imageanchor="1"><img border="0" height="384" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhszcm1iy_0pXOkEuu20SSWuWAk7fVUzdXvBQQyCKdtZ5RYdqeA-ZsuIoGWdcX5LCmo94MmcEk79zK5EsteyffX5slWXDhV8RjySJgd6omY5zw0r9scD67YII_24HIZO49Bei5bZDzzxKg/s640/posneg-any.png" width="640" /></a></div>
XPNPEP2 is of interest because its product's normal function (Aminopeptidase P) includes degrading bradykinin, also degraded by ACE2. The involvement of XPNPEP2 variants in ACE inhibitor-associated angioedema has been proposed as combining with the drug to produce <a href="https://www.omim.org/entry/300909?search=XPNPEP2&highlight=xpnpep2">higher circulating bradykinin</a>.<br />
<br />
Bradykinin <a href="https://innovationorigins.com/radboud-university-medical-center-ignites-international-research-into-essential-mechanism-in-the-disease-process-of-covid-19/">has already been suggested</a> as an important mediator of the COVID-19 because of <a href="https://www.preprints.org/manuscript/202004.0023/v1">clinical similarities between COVID-19 and ACE inhibitor induced angioedema</a>. Since SARS-CoV-2 gains entry to the cell via ACE2, the virus may <a href="https://www.bmj.com/content/368/bmj.m406/rr-19">inhibit its normal role and contribute to elevated bradykinin</a>. The dry cough associated with COVID-19 has been likened to the '<a href="http://www.pnmedycznych.pl/wp-content/uploads/2017/08/pnm_2017_440-446.pdf">bradykinin cough</a>' associated with the use of ACE inhibitors.<br />
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Interestingly, <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1312524">bradykinin inhibitors such as icatibant</a> already exist and are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603771/">used in ACE inhibitor induced angioedema</a>. However, to make the jump that such drugs might be useful against COVID-19 on this evidence alone is speculative, and there are several caveats to the association itself, including the requirement to replicate the effect in an independent population. There is a need to understand the robustness of the association to population stratification and other possible confounders.<br />
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Update</h3>
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<i>This post was updated a second time on 8 May to include inpatient status in the subgroup analysis.</i><br />
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To dig a little deeper into the result I have looked at effect sizes in different groups defined by</div>
<div>
<ul>
<li>Ethnicity: British (self reported), euranc (white European genetically) or any (these are the only groupings so far with sufficient sample size)</li>
<li>Sex: female, male or any</li>
<li>Close relatives: whether they are excluded (as above) or included in the analysis (larger sample size but potential for family clusters to over-influence the results)</li>
<li>Inpatients: whether individuals were in (ever inpatients when tested) or nin (never inpatients when tested)</li>
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The results suggest that the effect is both larger in magnitude and stronger in statistical significance in males. But this difference depends on inpatient status: the signal appears strong and similar in magnitude among male and female inpatients. In non-inpatients, the signal is non-significant in almost every subgroup. Including individuals not identified genetically as white European slightly dilutes the signal, as does including close relatives.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh-en5SbStcy7S0WnHPRy14QOPTAGSAdtCRZ5zamgA92v6InafbfbR_e-f_lYuvWOfUiN8dmDfn4zD331uxru3tFu5SuHvRiasFFrzga50qCJA4JurPisAYCg81149v4SLKrqG1qcinH88/s1600/forest2.png" imageanchor="1"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh-en5SbStcy7S0WnHPRy14QOPTAGSAdtCRZ5zamgA92v6InafbfbR_e-f_lYuvWOfUiN8dmDfn4zD331uxru3tFu5SuHvRiasFFrzga50qCJA4JurPisAYCg81149v4SLKrqG1qcinH88/s1600/forest2.png" /></a></div>
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The graph shows the effect (and 95% confidence interval) of the rarer allele: negative coefficients (on a log odds scale) indicate that the rare allele reduces the risk of returning a positive test. To illustrate, an effect size of -0.35 would imply that a male with the rare allele is 30% less likely to test positive than a male with the common allele.</div>
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Some technical details: the effect size analysis is based on a logistic regression, whereas the GWAS above uses the <a href="https://github.com/weizhouUMICH/SAIGE">SAIGE</a> tool. The covariates included are: sex, age, age*age, sex*age and genetic principal components (40 in the logistic regression, 20 in the GWAS). The results are being contributed to the <a href="https://www.covid19hg.org/">COVID-19 Host Genetics Initiative</a>.</div>
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Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-45626859749405964712020-05-07T02:45:00.000-07:002020-05-12T14:52:15.783-07:00Latest COVID-19 PCR test results for UK Biobank releasedThe latest tranche of COVID-19 PCR test result data for UK Biobank participants, collated from Public Health England data, has been released. This latest data covers the period March 16 - May 3. For details of how to access the data, see <a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html">this post</a>.<br />
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The updated data contains 5356 test results, 1806 of them positive. The tests correspond to 3002 participants, broken down as follows:<br />
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<ul>
<li>1073 returned one or more positive tests, of whom 825 returned tests while a hospital inpatient*</li>
<li>1929 never returned a positive test, of whom 1260 returned tests while a hospital inpatient</li>
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<span style="font-size: x-small;"><i>* This definition of COVID-19 positive inpatient does not require that the positive test and the test while an inpatient necessarily coincide in participants with multiple tests. Requiring them to coincide on the same test reduces this number from 825 to 818.</i></span><br />
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Here is a new version of Figure 4 of <a href="https://news.bugbank.uk/2020/04/updated-preprint-linking-covid-19-tests.html">our paper</a>, updated to reflect this latest tranche of test results. For a daily updating summary of lab-confirmed cases in England, visit <a href="http://coronavirus.data.gov.uk/">coronavirus.data.gov.uk</a>.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiWG7S67VzkGy0PgsonrTuu7k7ftIjH7iwAYR5Ep5SPfxVwnW635ZdwvBNrHEGyHn6Yb5zzlafSAxnEilt3OQGh6s27WWjdQuXWozZDbP3CMpecCwQUcxgItGvJutgYtDCtgDlaDAA7kSg/s1600/image001-2.jpg" imageanchor="1"><img border="0" height="432" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiWG7S67VzkGy0PgsonrTuu7k7ftIjH7iwAYR5Ep5SPfxVwnW635ZdwvBNrHEGyHn6Yb5zzlafSAxnEilt3OQGh6s27WWjdQuXWozZDbP3CMpecCwQUcxgItGvJutgYtDCtgDlaDAA7kSg/s640/image001-2.jpg" width="640" /></a><br />
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<br />Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com2tag:blogger.com,1999:blog-5536187228656752547.post-80631761053418022032020-04-19T13:26:00.000-07:002020-04-19T13:34:35.184-07:00Updated preprint: linking COVID-19 tests to UK BiobankMy bugbank colleagues and I have posted a <a href="https://doi.org/10.6084/m9.figshare.12091455">substantially revised preprint</a> describing our work linking COVID-19 test results between Public Health England's microbiology database SGSS and UK Biobank, the first data from which were released on Friday.<br />
<br />
I recommend reading this short paper for anyone interpreting these test results, because it describes the scientific rationale, the data limitations, and the basic epidemiological characteristics of the COVID-19 positive UK Biobank cohort.<br />
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<span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;">Armstrong, J., Rudkin, J. K., Allen, N., Crook, D. W., Wilson, D. J., Wyllie, D. H. and A.-M. O'Connell (2020)</span><br style="caret-color: rgb(51, 51, 51); color: #333333;" /><b style="caret-color: rgb(51, 51, 51); color: #333333;">Dynamic linkage of COVID-19 test results between Public Health's Second Generation Surveillance System and UK Biobank</b><br style="caret-color: rgb(51, 51, 51); color: #333333;" /><i style="caret-color: rgb(51, 51, 51); color: #333333;">Figshare</i><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;"> doi:10.6084/m9.figshare.12091455 (</span><a href="http://www.danielwilson.me.uk/abstracts/armstrong_etal_2020.html" style="color: #336699; text-decoration: none;">abstract</a><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;"> </span><a href="https://doi.org/10.6084/m9.figshare.12091455" style="color: #336699; text-decoration: none;">preprint</a><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;">)</span>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-54392850333978653342020-04-19T13:09:00.000-07:002020-04-19T13:20:04.744-07:00Suggestive hits for COVID-19 positive versus negative individuals<div class="separator" style="clear: both; text-align: left;">
<a href="https://www.mcgill.ca/endocrinology/facultydir/brent-richards">Brent Richards</a> of McGill University and colleagues had a different take on how to define cases of COVID-19 susceptible individuals and controls than <a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html">what I previously advocated</a>. They analysed only UK Biobank participants who had a test result, defining cases as those with at least one positive test, and controls as anyone whose test results were all negative (whether one test or multiple).</div>
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They and <a href="http://www.atgu.mgh.harvard.edu/people/andrea-ganna/">Andrea Ganna</a> suggested I take a look at this definition, and the new analyses throws up at least one very suggestive finding: a non-coding variant on the X chromosome in the <a href="https://genome-euro.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc011mum.2&hgg_prot=uc011mum.2&hgg_chrom=chrX&hgg_start=128872945&hgg_end=128882057&hgg_type=knownGene&db=hg19&hgsid=237654768_azJ4tyxrTmVjrgFCez1oeXQASaIR">XPNPEP2</a> gene. X-linked genes are of special interest because of the known elevated risk in males (who carry only one X chromosome) and the co-location of the <a href="https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2">ACE2</a> gene on chromosome X. ACE2 is a transmembrane protein by which SARS-CoV-2 (the COVID-19 virus) gains entry to cells.</div>
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Interestingly, variation in XPNPEP2 is said to confer susceptibility to <a href="https://www.omim.org/entry/300909?search=XPNPEP2&highlight=xpnpep2">ACE-inhibitor-induced angioedema</a>, an inflammatory reaction which causes <a href="https://www.tabers.com/tabersonline/view/Tabers-Dictionary/738504/all/angioedema">swelling and can lead to respiratory distress</a>. It is also interesting that ACE inhibitor drugs forge a connection between the X-linked ACE2 and XPNPEP2 genes.</div>
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Here are details of the analyses. I performed two analyses, one of which was focused only on white Europeans. The case:control ratios were 387:522 and 535:636 respectively. I controlled only for age, sex, and interaction between age and sex, and the first 10 or 40 principal components of genetic variation respectively. I controlled for population structure using <a href="https://github.com/weizhouUMICH/SAIGE">SAIGE</a>.</div>
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The Manhattan plot - where bigger numbers mean greater strength of evidence - for white Europeans shows two distinct peaks in chromsomes 3 and X. The most significant variant in both has a <i>p</i>-value of one in 10 million, which does not quite reach the conventionally agreed threshold for statistically interesting signals by a factor of two. However, <a href="https://news.bugbank.uk/2020/04/first-pass-analysis-of-human-genetic.html">sample sizes are set to increase</a>.</div>
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The hit on chromosome 3 (rs7637558) occurs in the <a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTPRG">PTPRG</a> gene, apparently involved in tumour suppression in some tissues. I have not yet looked into this signal in any detail. Brent and colleagues previously <a href="https://twitter.com/BrentRichards19/status/1251550109931888643?s=20">noted on twitter</a> this hit at a similar level of significance. They did not analyse the X chromosome.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjBv6mIaDJs0uibB9xbCETwyvZKUCsf8QK30o2nOMNFuCwVRPIQdEgtHmqH4Xh9oTHkK-mVUqnfSy92k7NGR3b600kjlDqSiz4m5whtRiBn_NKr07D1lhWaIZdznbMTiKrkR9KnkODsJCI/s1600/Manhattan-posneg-eur.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="961" data-original-width="1600" height="192" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjBv6mIaDJs0uibB9xbCETwyvZKUCsf8QK30o2nOMNFuCwVRPIQdEgtHmqH4Xh9oTHkK-mVUqnfSy92k7NGR3b600kjlDqSiz4m5whtRiBn_NKr07D1lhWaIZdznbMTiKrkR9KnkODsJCI/s320/Manhattan-posneg-eur.png" width="320" /></a></div>
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Here is a close-up of the X chromosome, with ACE2 marked by a grey vertical line. The peak of blue points is in XPNPEP2, with the most significant occuring at variant rs2076205.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgB4LofKDg8qfYHnp1yFHx-ryiGcviPjJWvfKUg847dSUABqcLlJSpRT68To12l87zWz5h14bWFKpjgru31eVyZCHwCrKMlmQwgCrd6jMfa3FkH_JyfwI0H7yoaSxe8e_goI2IhJuIBJ0E/s1600/Manhattan-posneg-eur-chrX.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="961" data-original-width="1600" height="192" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgB4LofKDg8qfYHnp1yFHx-ryiGcviPjJWvfKUg847dSUABqcLlJSpRT68To12l87zWz5h14bWFKpjgru31eVyZCHwCrKMlmQwgCrd6jMfa3FkH_JyfwI0H7yoaSxe8e_goI2IhJuIBJ0E/s320/Manhattan-posneg-eur-chrX.png" width="320" /></a></div>
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I have made initial efforts to check the results by re-analysing each variant using a simple logistic regression, which shows an expected dosage effect whereby individuals homozygous for the risk allele have a higher risk of being COVID-19 positive than heterozygotes.</div>
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Reassuringly, the top hit variant has a similar signal when analysing individuals of any ancestry. </div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEibYlPVl6EAEsFUCM_QYpj4ShuhmZjo8hG6HJ7w2XcBCegcsnOPu4taHFs3UlpGGTZcDZ05FFPUjji05rDl2v918GZg_VBzPtBavPd1rehPaGXSiouk8oSQxh0Ahb7Omx_Om-orAGPSyp0/s1600/Manhattan-posneg-all.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="961" data-original-width="1600" height="192" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEibYlPVl6EAEsFUCM_QYpj4ShuhmZjo8hG6HJ7w2XcBCegcsnOPu4taHFs3UlpGGTZcDZ05FFPUjji05rDl2v918GZg_VBzPtBavPd1rehPaGXSiouk8oSQxh0Ahb7Omx_Om-orAGPSyp0/s320/Manhattan-posneg-all.png" width="320" /></a></div>
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These results are as yet preliminary, and are subject to scrutiny via meta-analysis of different studies in the <a href="https://www.covid19hg.org/">COVID-19 Hg consortium</a> and as the number of cases continues to rise, as regrettably it will, in the UK Biobank cohort.</div>
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For aficionados, the SAIGE output for the top two hits is here:</div>
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<span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">SAIGE results, white Europeans:</span></div>
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<span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">CHR POS rsid SNPID Allele1 Allele2 AC_Allele2 AF_Allele2 imputationInfo N BETA SE Tstat p.value p.value.NA Is.SPA.converge varT varTstar AF.Cases AF.Controls</span></div>
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<span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">X 128893417 rs2076205 X:128893417_C_T C T 490.125490196078 0.269595979205764 0.990731443602318 909 -0.467221760698161 0.0880842712142245 -59.6888627031124 1.1313178853627e-07 1.28548802524349e-07 1 127.752745535483 130.654411688048 0.188812889496884 0.329486890541657</span></div>
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<span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">03 61708608 rs7637558 3:61708608_A_G A G 516.086274509803 0.283875838564248 0.989045376208952 909 -0.552085056361661 0.103915060855678 -50.6246662875149 1.07924297975498e-07 1.24547474669322e-07 1 91.6972225641108 93.7799545311091 0.218731316816132 0.332172639170611</span></div>
<br />Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0tag:blogger.com,1999:blog-5536187228656752547.post-55450423961652249512020-04-18T16:05:00.000-07:002020-04-18T16:05:15.320-07:00First pass analysis of human genetic susceptibility to severe COVID-19We have performed a preliminary analysis using UK Biobank COVID-19 data to test for genes or genetic variants that increase the risk of severe COVID-19. We have done several analyses but the conclusion is the same at this stage - the sample size is currently too small to distinguish true signals from noise. However, this may change over the next few weeks as (i) unfortunately, the number of cases will rise and (ii) the results from the UK Biobank cohort are combined with other cohorts through the <a href="https://www.covid19hg.org/">COVID-19 Hg initiative</a> using meta-analysis.<br />
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I will summarize just one of the analyses for brevity. The first analysis I tried was restricted to white European participants. Restricting the analysis this way is one approach to account for possible correlations between susceptibility to severe COVID-19 and genetic ancestry. I started with white Europeans because this is the largest group in the UK Biobank. I compared 330 cases of severe COVID-19 (identified as hospital inpatients with positive tests) to a control population of 283,722 participants with no known COVID-19, as described <a href="https://news.bugbank.uk/2020/04/interpreting-uk-biobank-covid-19-test.html">here</a>. I excluded individuals who did not live in England at the time of recruitment and individuals no longer followed up by UK Biobank. I also excluded individuals with genetic data that did not pass standard quality controls.<br />
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In the analyses so far, I have not yet accounted for most important epidemiological variables. Instead I have followed the COVID-19 Hg standard analysis plan which adjusts only for age and sex. In future iterations, we will address this limitation.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2LLjftWGOp0q0el5-HSblqeeVU4wzqq__8e7Z7GvjaRB9Wp6QWnBIdM2q72RoVu-ipKbZwViexXGX0sJNgXv7CcgWvcT53Em5wH3DtP_2u-P7pqYKVJxP-du9Ahmh1Np4_pDRAd4sLyQ/s1600/Manhattan-imp-2.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="961" data-original-width="1600" height="384" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2LLjftWGOp0q0el5-HSblqeeVU4wzqq__8e7Z7GvjaRB9Wp6QWnBIdM2q72RoVu-ipKbZwViexXGX0sJNgXv7CcgWvcT53Em5wH3DtP_2u-P7pqYKVJxP-du9Ahmh1Np4_pDRAd4sLyQ/s640/Manhattan-imp-2.png" width="640" /></a></div>
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The figure shows a Manhattan plot summarizing the location of signals of susceptibility to infection in the human genome. The bigger the peak, the stronger the evidence that genes in that region of the genome are associated with severe disease. No signal yet meets the stringent threshold for deeming it statistically interesting. The strongest signal so far is on chromosome 2. The closest gene is called KLHL29, which is involved in a wide variety of traits including obesity according to various studies in the <a href="https://www.ebi.ac.uk/gwas/genes/KLHL29">GWAS catalog</a>. The next strongest signal so far is on chromosome 14, near a gene called NRXN3 which is also involved in diverse traits, also including obesity according to the <a href="https://www.ebi.ac.uk/gwas/genes/NRXN3">GWAS catalog</a>. If these turn out to be statistically interesting signals, it supports predictions that the analysis is likely to pick up genetic susceptibility to pre-disposing factors, of which obesity is one. This underlines the importance of controlling for such mediating risk factors in future analyses.<br />
<br />Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com8tag:blogger.com,1999:blog-5536187228656752547.post-17840480877047262832020-04-18T09:51:00.001-07:002020-06-05T13:35:50.270-07:00Interpreting UK Biobank COVID-19 test dataFollowing the <a href="https://www.ukbiobank.ac.uk/2020/04/covid">press release</a> earlier this week, UK Biobank have released the COVID-19 lab-confirmed test results for English participants that we helped link from Public Health England's Second Generation Surveillance System. In this post I describe how the data is obtained and make some recommendations for interpreting the test results.<br />
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<h3>
Registering for the data</h3>
To access the data, you need to be a <a href="https://www.ukbiobank.ac.uk/register-apply/">registered researcher</a> attached to an approved project. (This can be a lengthy process.)<br />
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UK Biobank emailed existing researchers this week with information on how to access the new data: "<i>If you wish to receive the primary care data restricted for COVID-19 research purposes, or the more frequent updates of other health outcome data, then please go to UK Biobank's Access Management System (AMS) and go to the Data tab of your Project/Application where you will find a button that takes you to a sign-up page for requesting these data. </i><br />
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<i>"Researchers requiring access to the primary care data will be asked to confirm that they will only use them for COVID-19 related research. The Application's Principal Investigator on an approved project will need to sign-up to apply for these data before they will be released.</i>"<br />
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Downloading the data</h3>
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UK Biobank have created <a href="http://biobank.ndph.ox.ac.uk/ukb/exinfo.cgi?src=COVID19">instructions</a> explaining how researchers with existing projects who have successfully registered for additional access to COVID-19 data can download it.</div>
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Downloading the data is through the data portal, which requires some knowledge of SQL. To download (<i>updated 5 June 2020</i>):</div>
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<li>Log in as usual at <a href="http://bbams.ndph.ox.ac.uk/">bbams.ndph.ox.ac.uk</a> </li>
<li>Navigate to your <b>Project</b></li>
<li><b>View/Update</b> it</li>
<li>Click the <b>Data</b> tab</li>
<li>Select the <b>Go to Showcase to refresh or download data</b> button</li>
<li>Select the <b>Data Portal</b> tab</li>
<li>Click <b>Connect</b></li>
<li>At the bottom of the page, click the <b>Table Download</b> tab</li>
<li>In the Name of table box, enter <b><span style="font-family: "courier new" , "courier" , monospace;">covid19_result</span></b> and click <b>Fetch Data</b></li>
<li>Click the link produced to download the file.</li>
</ul>
</div>
<div>
<h3>
Interpreting the data</h3>
</div>
<div>
NB: a description of the data format <a href="http://biobank.ndph.ox.ac.uk/ukb/exinfo.cgi?src=COVID19_tests">has been provided by UKB.</a> The data format and definitions <b>may change</b>.</div>
<div>
<br /></div>
<div>
The data look like this:</div>
<div>
<blockquote class="tr_bq">
</blockquote>
</div>
<div>
<table border="0" cellpadding="0" cellspacing="0" style="border-collapse: collapse; color: black; width: 522px;"><colgroup><col span="6" style="width: 65pt;" width="87"></col></colgroup><tbody>
<tr height="21" style="height: 16pt;"><td height="21" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; height: 16pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">eid</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">specdate</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">spectype</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">laboratory</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">origin</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">result</span></td></tr>
<tr height="21" style="height: 16pt;"><td height="21" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; height: 16pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">XXXXXXX</span></td><td class="xl63" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">29/03/2020</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">1</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">9</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">1</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">1</span></td></tr>
<tr height="21" style="height: 16pt;"><td height="21" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; height: 16pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">XXXXXXX</span></td><td class="xl63" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">29/03/2020</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">2</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">10</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">1</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">0</span></td></tr>
<tr height="21" style="height: 16pt;"><td height="21" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; height: 16pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">XXXXXXX</span></td><td class="xl63" style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">31/03/2020</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">2</span></td><td style="border: none; font-family: Calibri, sans-serif; font-size: 12pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">10</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">0</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">1</span></td></tr>
</tbody></table>
</div>
<div>
<br /></div>
<div>
The first thing to notice is that each row of the data refers to a COVID-19 <b>test</b>. So most users will need to reinterpret that table at the level of an <b>individual participant</b>, using the <span style="font-family: "courier new" , "courier" , monospace;">eid</span> column.</div>
<div>
<br /></div>
<div>
Here I will explain how my colleagues and I envisage the data being used, which will be explained in more detail in draft 2 of the preprint. We believe the data are suited for addressing the question <i>Why do some people suffer from severe COVID-19?</i> For statistical analyses, we are defining:</div>
<div>
<ul>
<li>A case as anyone with <b>severe</b> <b>COVID-19</b>: any person with at least one positive test while an inpatient. This means anyone with one or more test results with <span style="font-family: "courier new" , "courier" , monospace;">origin=1</span> (inpatient) <span style="font-family: "courier new" , "courier" , monospace;">AND</span> <span style="font-family: "courier new" , "courier" , monospace;">result=1</span> (infected).</li>
<li>A control as anyone <b>not known to have COVID-19</b>: any person with no positive test results at all. This means anyone with no tests or anyone whose tests were all negative (<span style="font-family: "courier new" , "courier" , monospace;">result=0</span>).</li>
<li>An excluded person as anyone with COVID-19 of unknown severity: any person with at least one positive test but never while an inpatient.</li>
</ul>
</div>
<div>
The reason for defining cases this way is because UK policy since 16 March 2020 has been to admit to hospital only patients with severe disease. To help define severe cases only, no test results have been included before this date. Many individuals with positive tests who were not hospital inpatients at the time of the test are likely to be healthcare workers, so they did not necessarily have severe disease. We are assuming that members of the control group (anyone not known to have COVID-19) have not been exposed, or have not suffered severe disease.</div>
<div>
<br /></div>
<div>
In the first tranch of data, using the above definitions, there were 572 cases, 97 excluded participants and 805 participants mentioned in the results file but never tested positive who therefore qualify as controls. <i><span style="color: #999999;">[This article previously incorrectly said that all 97+805=902 non-cases in the results file were excluded participants.]</span></i></div>
<div>
<br /></div>
<div>
Note that only test results in England are reported. One way of excluding individuals who cannot be cases because they do not live in England is to assume participants live in the same country as the recruitment centre they originally attended. Assessment centre at recruitment is <a href="http://biobank.ndph.ox.ac.uk/ukb/field.cgi?id=54">field 54</a>, and the following are the codes for English recruitment centres:</div>
<div>
<table border="0" cellpadding="0" cellspacing="0" style="border-collapse: collapse; color: black; width: 174px;"><colgroup><col span="2" style="width: 65pt;" width="87"></col></colgroup><tbody>
<tr height="24" style="height: 18pt;"><td height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; text-align: right; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11012</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap; width: 65pt;" width="87"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Barts</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11021</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Birmingham</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11011</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Bristol</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11008</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Bury</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11024</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Cheadle</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11020</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Croydon</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11018</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Hounslow</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11010</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Leeds</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11016</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Liverpool</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11001</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Manchester</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11017</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Middlesborough</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11009</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Newcastle</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11013</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Nottingham</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11002</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Oxford</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11007</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Reading</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11014</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Sheffield</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">10003</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Stockport</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11006</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Stoke</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11025</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Cheadle</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11026</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Reading</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11027</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Newcastle</span></td></tr>
<tr height="24" style="height: 18pt;"><td align="right" height="24" style="border: none; height: 18pt; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">11028</span></td><td style="border: none; padding-left: 1px; padding-right: 1px; padding-top: 1px; vertical-align: bottom; white-space: nowrap;"><span style="font-family: "courier new" , "courier" , monospace; font-size: xx-small;">Bristol</span></td></tr>
</tbody></table>
</div>
For me, this removed 56,650 participants, none of whom had test results (as expected). Excluding other participants who cannot be cases, such as those lost to follow-up, is also recommended.<br />
<br />Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com6tag:blogger.com,1999:blog-5536187228656752547.post-49863327991843891852020-04-15T07:59:00.000-07:002020-04-15T07:59:07.111-07:00UK Biobank announces COVID-19 initiativeUK Biobank have announced that results of COVID-19 tests for UK Biobank participants, including confirmed cases, are being provided through Public Health England, and will shortly be available for research: <a href="https://www.ukbiobank.ac.uk/2020/04/covid">https://www.ukbiobank.ac.uk/2020/04/covid</a><br />
<br />
Other data will follow:<br />
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<ul>
<li>GP (primary care) data on a monthly basis for COVID-19 related research. It will be provided via GP system suppliers EMIS Health and TPP which cover about 95% of GP practices in England. Similar updates from Wales and Scotland are expected;</li>
<li>Hospital episodes (HES) data and death data on a monthly basis;</li>
<li>Intensive care (ICNARC) data.</li>
</ul>
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<br />Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com1tag:blogger.com,1999:blog-5536187228656752547.post-58246183245073930582020-03-22T15:44:00.003-07:002020-03-22T15:44:49.893-07:00UK Biobank - PHE microbe database linkage paperUploaded this week on medRxiv, the first preprint describing periodic linkage between Public Health England's microbiology database - the second generation surveillance system, SGSS - and UK Biobank. Note that a second paper is in preparation describing frequent - up to daily - linkage.<br />
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<b style="caret-color: rgb(51, 51, 51); color: #333333;">Microbial isolation in English participants in the UK Biobank cohort: comparison with the general population</b><br style="caret-color: rgb(51, 51, 51); color: #333333;" /><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;">Hilton, B., Wilson, D. J., O'Connell A.-M., Ironmonger, D., Rudkin, J. K, Allen, N. and D. Wyllie (2020)</span><br style="caret-color: rgb(51, 51, 51); color: #333333;" /><i style="caret-color: rgb(51, 51, 51); color: #333333;">medRxiv</i><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;"> </span><b style="caret-color: rgb(51, 51, 51); color: #333333;">doi</b><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;">:10.1101/2020.03.18.20038281 (</span><a href="http://www.danielwilson.me.uk/abstracts/hilton_etal_2020.html" style="color: #336699; text-decoration: none;">abstract</a><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;"> </span><a href="https://www.medrxiv.org/content/10.1101/2020.03.18.20038281v1" style="color: #336699; text-decoration: none;">preprint</a><span style="background-color: white; caret-color: rgb(51, 51, 51); color: #333333;">)</span>Daniel Wilsonhttp://www.blogger.com/profile/04144378927140578198noreply@blogger.com0