Saturday, 27 February 2021

The Cambridge study testing asymptomatics is the gift that keeps on giving ....

This makes interesting reading for anybody who still believes the Government 'case' data and the claim that just because you don't have any COVID-19 symptoms it doesn't mean you aren't an danger ...

This data also means that if the Government claim that “1 in 3 people with the virus has no symptoms” is correct then the ONS estimated infection rate is massively inflated - the currently reported ‘case’ numbers must be at least 8 times greater than the true number of cases. On the other hand, if the Government estimates of case numbers are correct then at most 1 in 26 people with the virus has no symptoms.  Here's an informal explanation why (formal proof is below):

Cambridge has a population of 129,000.

If the ONS infection estimates for Cambridge (0.71%) are accurate, then during an average week in this period about 916 people had the virus and 128,084 did not. 

But if the “1 in 3” claim is correct about 305 people in Cambridge had the virus but no symptoms. 

So at most 128,389 people in Cambridge had no symptoms and that means at least 305/128389 people with no symptoms had the virus. That is at least 0.24% (i.e. at least around 1 in 421). 

But the study shows on average only 1 in 4867 (0.028%) with no symptoms had the virus. So there should only have been about 36. 

That means the “1 in 3” claim and the ONS estimates cannot both be correct. 

If the “1 in 3” claim is correct, then the maximum possible value for the infection rate is 0.084% and not 0.71% as claimed (with 0.084% we would have 108 with the virus of whom 36 have no symptoms). So the ONS estimated infection rate is over 8 times greater than the true rate. 

If the 0.71% infection rate is correct, then the maximum possible value for the proportion of people with the virus who have no symptoms is 3.9% (as this would mean 36 of the 916 people with the virus have no symptoms as predicted by the Cambridge data).

 



Conclusions:

  • Although the above analysis applied to a single UK city, there is no reason to believe it' is special (see the report below on national lateral flow testing data).   
  • Since mass PCR testing began many of those classified as 'cases' were not COVID-19. And the Government claim that "1 in 3 with the virus has no symptoms" is massively exaggerated.  There needs to be confirmatory testing for any people testing positive before they are declared a 'case'.
  • We should stop testing people without symptoms unless they have been in recent contact with a person confirmed as having the virus.
  • And it's always interesting to compare number of NHS 999 emergency COVID-19 calls/triages with number of 'cases'. This data (digital.nhs.uk/dashboards/nhs) clearly shows real pandemic last spring but not '2nd/3rd waves'. All caveats discussed here probabilityandlaw.blogspot.com/2021/01/more-o apply


Also: This Government report says 9,480 of 2,372,358 lateral flow tests in UK 28 Jan - 3 Feb were positive. It is assumed almost all lateral flow tests are on people without symptoms. Given the false positive rate for these tests that's about 1 in 1587 true positives. In the same period the ONS estimated UK infection rate was 1 in 77.  

Obviously all of this data is on asymptomatics tested, so we expect the percentage testing positive to be less than the overall infection rate. However, this data still massively contradicts Government claims about asymptomatics as explained here.

And, of course, we have very solid evidence that the number of 'cases' based on PCR testing are inflated.

The links: 





Wednesday, 24 February 2021

COVID-19 risk to Jews

From last year's ONS report. These figures are before adjusting for age and multiple other factors

 

The increased risk of COVID-19 to the BAME community has been very widely discussed. There are doubts about the extent to which socio-economic factors, rather than genetic factors, explain the increased death risk and - as we pointed out in this article - there are also doubts about the way the risk is analysed and presented which can lead to exaggerations.  

Much less discussed is the increased risk to the Jewish community. In July we noted that the ONS report on COVID-19 risk by religion highlighted the increased risk to Muslims, even though the data suggested that Jews were the religious group with the highest risk of death. A new study provides further evidence that it is, indeed, Jews who have the highest risk of death from COVID-19.

 The study by Gaughan et al concludes

The majority of the variation in COVID-19 mortality risk was explained by controlling for sociodemographic and geographic determinants; however, those of Jewish affiliation remained at a higher risk of death compared with all other groups. 

Another study by Gaskell et al focuses on the orthodox Jewish community and confirms that there is an especially high prevelance of COVID-19 among this community. 

Thanks to Dr Robin Goodwin for alerting me to the new publications. 

Full details:



UK lighthouse laboratories testing for SARS-COV-2 may have breached WHO Emergency Use Assessment and potentially violated Manufacturer Instructions for Use


 

If you have been following the coverage on this blog about Covid-19 false positives you will be interested to read that we have recently discovered that UK laboratories have been routinely recording a large proportion of Covid-19 test results as positive based on the presence of one target gene alone, when there should have been two or more, as required to comply with WHO rules and manufacturer instructions. For example, an average of 35% across the whole of the UK during week of 25 Jan 2021 were based on one gene only. Obviously, there is higher risk of encountering false positives when testing for single genes alone, because of the possibility of cross-reactivity with other HCOVs and prevalent nasopharyngeal bacteria or reagent contamination. Unless UK laboratories have performed diagnostic validation of their single gene call, for both the original and the B1.1.7 variant, and there is no evidence of this in the public domain, it can only be assumed that, in the absence of confirmatory testing, many of the reported positive results may in fact be inconclusive, negative or from people who suffered past infection for SARS-COV-2.

An academic pre-print of article available here

The full article is reproduced below:

  

Positive results from UK single gene testing for SARS-COV-2 may be inconclusive, negative, or detecting past infections

Prof. Martin Neil, School of Electronic Engineering and Computer Science, Queen Mary, University of London

25 February 2021 (version 2)

 

Abstract

The UK Office for National Statistics (ONS) publish a regular infection survey that reports data on positive RT-PCR test results for SARS-COV-2 virus. This survey reports that a large proportion of positive test results are based on the detection of a single gene rather than on two or more genes as required in the manufacturer instructions for use, and by the WHO in their emergency use assessment. The proportion of positives called on single genes increased from mid-November to mid-December 2020, suggesting a shift in testing policy coincident with the reported significant increase in transmission of the new variant B1.1.7, and again starting January 2021. Without diagnostic validation of the single gene call, for both the original and the B1.1.7 variant it can only be assumed that, in the absence of confirmatory testing, many of the reported positive results may in fact be inconclusive, negative or from people who suffered past infection for SARS-COV-2.

 

Background

The ONS publish a regular infection survey [1] that includes data from two UK lighthouse laboratories, based in Glasgow and Milton Keynes, where both use the same RT-PCR test kit, to detect the SARS-COV-2 virus. This survey includes data on the cycle threshold (Ct) used to detect positive samples, the percentage of positive test results arising from using RT-PCR, and the combinations of the SARS-COV-2 virus genes tested that gave rise to positives between 21 September 2020 and 30 January 2021 across the whole of the UK.

ThermoFisher TaqPath kit[1] is used by the Glasgow and Milton Keynes lighthouse laboratories to test for the presence of three genes from SARS-COV-2[2]. Despite Corman et al [2] originating the use of PCR testing for SARS-COV-2 genes[3] there is no agreed international standard for SARS-COV-2 testing. Instead, the World Health Organisation (WHO) leaves it up to the manufacturer to determine what genes to use and merely requires end users to adhere to the manufacturer instructions for use (IFU). As a result of this we now have an opaque plethora of commercially available testing kits, that can be applied using a variety of test criteria. Other UK laboratories use different testing kit, and test for different genes.

The WHO’s emergency use assessment (EUA) for the ThermoFisher TaqPath kit [3], used by the Glasgow and Milton Keynes lighthouse laboratories, includes the instruction manual and contained therein is an interpretation algorithm describing an unequivocal requirement that two-or-more genes be detected before a positive result can be declared. The WHO have been so concerned about correct use of RT-PCR kit that on 20 January 2021 they issued a notice for PCR users imploring them to review manufacturer IFUs carefully and adhere to them fully [4].

Increasing proportion of single gene “calls”

The ONS’s report [1] lists SARS-COV-2 positive results for valid two and three gene combinations[4] from the Glasgow and Milton Keynes lighthouse laboratories. However, it also lists inconclusive single gene detections as positive results[5]. This use of single gene “calls” therefore suggests that Glasgow and Milton Keynes lighthouse laboratories may have breached WHO emergency use assessment (EUA) and may have violated the manufacturer instructions for use (IFU). Indeed, Section 10 of this ONS Covid-19 Infection survey on the 8 January 2020 [16] stated that (emphasis mine):

“Swabs are tested for three genes present in the coronavirus: N protein, S protein and ORF1ab. Each swab can have any one, any two or all three genes detected. Positives are those where one or more of these genes is detected in the swab …..”

Over the period reported the maximum percentage of positives on a single gene is 35% for the whole of the UK for the week of 25 January. The overall UK average is 21%. The maximum percentage reported is 65%, in East England in the week beginning 5 October. In Wales it is 48%, in Northern Ireland it is 47% and in Scotland it is 49%. The full data including averages and maxima/minima are given in Table 1.

Figures 1 and 2 show the percentage of weekly single gene positives across the UK nations and English regions. There was a significant peak across the whole of the UK (except NI) from mid-November to early December, coincident with the reported significant increase in transmission of the new variant B1.1.7 [5]. However, given this new variant was concentrated in Kent and NE London, with limited spread into the rest of London, Anglia and Essex its presence cannot explain why single gene calls increased in other regions such as the North East and Yorks. & Humber. There has been another significant increase in the percentage of single gene positives since the end of 2020, rising throughout January, and here the rise is steady across all English regions and UK nations.

In startling contradiction to the ONS reports Professor Alan McNally, Director of the University of Birmingham Turnkey laboratory, who helped set up the Milton Keynes lighthouse laboratory, reported in the Guardian newspaper, in an article about the new variant, that all lighthouse laboratories operated a policy that adhered to the manufacturer instructions for use: requiring two-or-more genes for positive detection [6] (this policy is also documented in the supplementary material provided in [7]).



Table 1: Percentage of weekly single gene positives from 21 September 2020 to 25 January 2021, including averages and maxima/minima


 

Figure 1: Percentage of weekly single gene positives from 21 September 2020 to 25 January 2021 (UK nations)

 


Figure 2: Percentage of weekly single gene positives from 21 September 2020 to 25 January 2021 (English regions)

In April 2020, the UK lighthouse laboratories were testing for single genes and discounted the S gene as early as mid-May, months before the discovery of the new variant B1.1.7 (emphasis mine):

“Swabs were analysed at the UK’s national Lighthouse Laboratories at Milton Keynes (National Biocentre) (from 26 April) and Glasgow (from 16 August) …., with swabs from specific regions sent consistently to one laboratory. RT-PCR for three SARS-CoV-2 genes (N protein, S protein and ORF1ab) ..... Samples are called positive in the presence of at least single N gene and/or ORF1ab but may be accompanied with S gene (1, 2 or 3 gene positives). S gene is not considered a reliable single gene positive (as of mid-May 2020).”

Indeed, in Table 1 of [17] 18% of tests were positive on one gene only and it was concluded, in Table 2 of [17], that for people with single gene positives, when Ct > 34, none had symptoms and for people with Ct < 34 only 33% had symptoms.

Furthermore in [16], published January 8th 2021, it states the goal of using one gene was explicitly to approximate the growth of the new variant (emphasis mine):

“There has recently been an increase in the percentage of positive cases where only the ORF1ab- and N-genes were found and a decrease in the percentage of cases with all three genes. We can use this information to approximate the growth of the new variant.”

Quality control and cross reactivity

Quality control problems have already been reported in UK laboratories [8, 9, 10] and there have been concerns expressed about the potential for false positives arising consequently. Recent suspicion focused on problems potentially caused by breaches in acceptable Ct thresholds (Ct > 37), suggesting no, or past, infection. However, this new ONS data shows there may be an additional potentially dominant source of false positives, at least within the period covered by the ONS report, if not from April 2020; specifically, positives caused by potential breach of WHO end user assessment and manufacturer instructions for use. These sources of false positives appear not to be caused by statistical error but might instead be categorised as systematic non-compliance.

Concerns about testing in commercial laboratories were documented by the ONS as early as May 2020 [11], when the REACT study discovered that circa 40% of positive tests from commercial laboratories were in fact false positives. A similar false positive rate (44%) was reported in Australia [12] in April 2020.  More recently Nicholas Lewis claims that, despite very low false positive rates (0.033%) from testing done by non-commercial and academic laboratories, there may be good reason to suspect the operational false positive rates from lighthouse laboratories are worse than these by some orders of magnitude [13].

Obviously, there is higher risk of encountering false positives when testing for single genes alone, because of the possibility of cross-reactivity with other HCOVs and prevalent nasopharyngeal bacteria or reagent contamination. The potential for cross reactivity when testing for SARS-COV-2 has already been confirmed by the German Instand laboratory report from April 2020 [14]. This report describes the systematic blind testing of positive and negative samples anonymously sent to many laboratories throughout Germany and evaluated for the presence of a variety of genes associated with SARS-COV-2[6]. They reported significant cross reactivity and resultant false positives for OC43, and HCoV 229E (a common cold virus) as well as for SARS-COV-2 negative samples, not containing any competing pathogen.

It should be noted that these issues are not unique to the UK. Likewise, 70 Dutch laboratories were surveyed in November 2020 [15], by the National Institute for Public Health and the Environment, with 76 diagnostic workflows reported as using only one target gene to diagnose the presence of SARS-COV-2 (46% of all workflows).

Conclusions

Unless the UK lighthouse laboratories have performed diagnostic validation of their single gene call, for both the original and the B1.1.7 variant, and there is no evidence of this in the public domain, it can only be assumed that, in the absence of confirmatory testing, many of the reported positive results may be inconclusive, negative or from people who suffered past infection for SARS-COV-2. Even with diagnostic validation of the single gene call, the UK lighthouse laboratories appear to be in breach of both the WHO emergency use assessment and, also, to have potentially violated the ThermoFisher TaqPath kit instructions for use.

 

 

 

 

 

References

[1] Steel K. and Fordham E. Office for National Statistics. Coronavirus (Covid-19) Infection Survey. 5 December 2020.

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/datasets/coronaviruscovid19infectionsurveydata

[2] Corman V., Landt O. et al “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR” Euro Surveillance. 2020 Jan;25(3):2000045. doi: 10.2807/1560-7917.ES.2020.25.3.2000045.

[3] WHO Emergency Use Assessment Coronavirus disease (COVID-19) IVDs. PUBLIC REPORT. Product: TaqPath COVID‑19 CE‑IVD RT‑PCR Kit. EUL Number: EUL-0525-156-00. Page 60

https://www.who.int/diagnostics_laboratory/eual/200921_final_pqpr_eul_0525_156_00_taqpath_covid19_ce_ivd_rt_pcr_kit.pdf?ua=1

[4] WHO Information Notice for IVD Users 2020/05. Nucleic acid testing (NAT) technologies that use polymerase chain reaction (PCR) for detection of SARS-CoV-2. 20 January 2021

https://www.who.int/news/item/20-01-2021-who-information-notice-for-ivd-users-2020-05

[5] Public Health England “Investigation of novel SARS-COV-2 variant”, 202012/01.

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/959438/Technical_Briefing_VOC_SH_NJL2_SH2.pdf

[6] Alan McNally. “It's vital we act now to suppress the new coronavirus variant” Opinion section the Guardian Newspaper, 22 Dec 2020. https://amp.theguardian.com/commentisfree/2020/dec/22/new-coronavirus-variant-b117-transmitting?CMP=Share_AndroidApp_Other&__twitter_impression=true

[7] Richter, A., Plant, T., Kidd, M. et al. How to establish an academic SARS-CoV-2 testing laboratory. Nat Microbiol 5, 1452–1454 (2020). https://doi.org/10.1038/s41564-020-00818-3

[8] Daily Mail “Chaos in Britain’s Covid labs: Scientist lifts lid on government facilities. 18 September 2020.

https://www.dailymail.co.uk/news/article-8746663/Chaos-Britains-Covid-labs-Scientist-lifts-lid-government-facilities.html

[9] Channel 4 Dispatches: Lockdown Chaos: How the Government Lost Control. 15th November 2020

https://origin-corporate.channel4.com/press/news/dispatches-uncovers-serious-failings-one-uks-largest-covid-testing-labs

[10] BBC News: Coronavirus testing lab 'chaotic and dangerous', scientist claims. 16 October 2020.

https://www.bbc.co.uk/news/health-54552620

[11] Riley S. Kylie E, Ainslie O. et al. Community prevalence of SARS-CoV-2 virus in England during May 2020: REACT study. July 2020. https://www.medrxiv.org/content/10.1101/2020.07.10.20150524v1

[12] Rahman, H., Carter, I., Basile, K., Donovan, L., Kumar, S., Tran, T., ... & Rockett, R. (2020). Interpret with caution: An evaluation of the commercial AusDiagnostics versus in-house developed assays for the detection of SARS-CoV-2 virus. Journal of Clinical Virology, 104374

[13] Lewis. N. “Rebuttal of claims by Christopher Snowden about False Positive Covid-19 test results”. February 2020. https://www.nicholaslewis.org/a-rebuttal-of-claims-by-christopher-snowdon-about-false-positive-covid-19-test-results/

[14] Zeichhardt H., and Kammel M. “Comment on the Extra ring test Group 340 SARS-Cov-2” Herausgegeben von: INSTAND Gesellschaft zur Förderung der Qualitätssicherung in medizinischen Laboratorien e.V. (INSTAND Society for the Promotion of Quality Assurance in Medical Laboratories e.V.) 3rd June 2020.

https://www.instand-ev.de/System/rv-files/340%20DE%20SARS-CoV-2%20Genom%20April%202020%2020200502j.pdf

[15] External Quality Assessment of laboratories Performing SARS-CoV-2 Diagnostics for the Dutch Population. National Institute for Public Health and the Environment, Ministry of Health, Welfare and Sport., November 2020.

[16] ONS Coronavirus (COVID-19) Infection Survey, UK: 8 January 2021. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/coronaviruscovid19infectionsurveypilot/8january2021#the-percentage-of-those-testing-positive-who-are-compatible-for-the-new-uk-variant

[17] Walker S. Pritchard E et al. Viral load in community SARS-CoV-2 cases varies widely and temporally.  https://www.medrxiv.org/content/10.1101/2020.10.25.20219048v1

 



[1] The full name for ThermoFisher TaqPath kit is TaqPath COVID‑19 CE‑IVD RT‑PCR.

[2] N, S and ORF1ab genes

[3] Corman et al recommended the E, N and RdRp genes

[4] N+S+ORF, ORF+S, N+S and N+ORF gene combinations

[5] N alone, ORF alone (note that the S gene is included in the ONS analysis but is never counted as a positive if it is detected in isolation)

[6] N, E, S, ORF1a, ORF1ab and RdRP