GIS2 at Ryerson

[Skip to second paragraph if you are not interested in the German context of the false positives issue.]

On June 5, 2020, OVALMedia’s Robert Cibis interviewed the Austrian microbiologist and infectious disease specialist Dr. Martin Haditsch about laboratory tests and specifically the PCR test that is used globally to detect the Sars-CoV-2 virus in a person. The interview [in German] broached the issue of false-positive test results in the context of a low-prevalence disease and imperfect tests. Two Youtube copies of the one-hour interview have a total of over 100,000 views at the time of writing. The next day, Swiss entrepreneur and Youtuber Samuel Eckert presented a 20-minute summary and explanation of the false-positive issue using an interactive Excel spreadsheet. His video currently boasts over 225,000 views with 15,000 likes. Possibly in response, the German Federal Minister of Health Jens Spahn, a banker by training, said in a brief interview contained in a tweet from public TV channel ARD on June 14 that if the COVID-19 prevalence continued to drop and testing was simultaneously expanded (as has been the case in many Western countries since mid-April) into the millions then you would eventually obtain more false-positive than correct-positive results.

Six weeks later, in a media briefing about the Province of Ontario’s safe reopening of schools, Associate Chief Medical Officer of Health Dr. Barbara Yaffe cautioned against seeing wide-spread COVID-19 testing as a solution. She went on to state that “in fact, if you’re testing in a population that doesn’t have very much COVID, you’ll get false positives almost half the time.”

http://gis.blog.ryerson.ca/files/2020/09/Ontario-announces-details_July-30_Trim2.mov

In order to understand the impact of two test characteristics – sensitivity and specificity – we can use a confusion matrix to display true and false positive test results along with true and false negative test results. For example, in Geography we use confusion matrices to assess the accuracy of the classification of a remotely sensed image. The confusion matrix shows how many pixels of a certain land use class such as agricultural were correctly classified as agricultural or misclassified as another land use like forest. This is based on a ground-truthed image for comparison in a limited part of the study area. Similarly, the following spreadsheet estimates how often a positive or negative PCR test result is found in a true carrier of the virus vs an unaffected person.

https://drive.google.com/file/d/1S-Ae_OT4bnxct8_V_s2pxFp0R0FO73nA/view?usp=sharing

The true proportions and counts of “infected” and not “infected” are based on the number of tests completed and the true prevalence of COVID-19 in the population, which is largely unknown. At the tail end of winter, coronaviruses are typically causing cold infections in some 5% to 10% of the population. As COVID-19 has tapered off over the summer, a value below 1% seems reasonable, here set to 0.5% as an example. In recent days, there were 40,000 or more tests completed in Ontario with some 400 new “cases” detected for a test-positivity rate of around 1%. Note that in conjunction with the PCR test, I like to put “cases” and “infected” in quotation marks since the test does not distinguish sick people carrying an infectious virus load from healthy, presymptomatic, or asymptomatic people carrying traces of inactive genetic material from the virus.

With a prevalence of e.g. 0.5%, we expect that 200 out of 40,000 tests are true positives. If we assume the sensitivity characteristic of the test at 99%, we get 198 correct positives out of the 200 true “infections” that should be detected, while two are missed. These two misses are false-negative results. False negatives are problematic, since potentially infectious persons are told that they don’t pose a risk to their environment. However, at a low prevalence of the disease, these misses are very small, even negligible, in comparison with the correctly identified negatives.

After subtracting 200 “infected” from the 40,000 tests completed, there are 39,800 left who should test as not “infected”. However, medical tests are usually imperfect in that they can both miss a condition present (false negatives, see above) as well as indicate the presence of a condition when it is not there (false positives). The characteristic that describes how accurate the test is in this latter respect is called specificity. It refers to how specific the test is geared towards its target, here the Sars-CoV-2 virus, rather than picking up other targets. The specificity of the PCR test for Sars-CoV-2 is a bit of a mystery and moving target, but before I discuss it, I will go through one example to explain the significance of false-positive results in the current phase of the pandemic.

With an assumed specificity of 99.5%, our test would determine 39,601 correct negatives out of 39,800 persons who are truly not “infected”. An issue arises with the remaining 199 false positives, which are wrongly detected by the test although they do not carry the virus. While the number is small in proportion to the correct negatives, we need to view it in relation to the 198 correct positives. From the perspective of each person testing positive, the chance that they are in fact falsely positive is 199 : 198, thus 50% of the 397 total positive test results are false positives, in line with the warnings by the officials cited above. The relationship is only this large due to the low prevalence of the disease. You can use the spreadsheet link above to examine the effect of increasing or decreasing the prevalence (try 0%!) and modifying the test characteristics.

Due to the significant restrictions imposed on test-positive persons’ lives, 50% false positives is a highly problematic proportion. In addition, a difference between 200 and 400 new “cases” may affect the assessment of the current public health threat, although the raw count of positive PCR tests is almost meaningless without considering who was tested and how many tests were completed, an issue which shall be discussed at another time.

Some critics of the pandemic response are using a lower specificity of 98.6% and come to the conclusion that all (!) positive test results in certain jurisdictions such as Germany are false positives and therefore the pandemic has ended. That values stems from a study of lab results (external PDF, see page 12) conducted by a German accreditation body in April, which found an average of 98.6% correct negative results across over 400 participating labs. Other experts however have noted that the actual proportions of positive test results has gone down to values as low as 0.6% in Germany, 0.3% in Canada, and even 0% in New Zealand, which – given the large numbers of tests completed – would not be possible if the false positives were any higher than these values. This can be explained by the fact that the quality assurance study reported the results for individual gene sequences but the testing protocols in some countries were modified to require testing of at least two gene sequences. In this case, the false positive rates of 0.5% for the E gene region (which I used in the above example) and e.g. around 2% for another characteristic gene would have to be multiplied, resulting in extremely low false-positives of 1 in 10,000 or so. However, Public Health Ontario’s in-house test methods target the E gene and clearly state that “Specimens with a single target detected … will be reported as COVID-19 virus detected, which is sufficient for laboratory confirmation of COVID-19 infection.” (emphasis added)

In summary, false-positive PCR test results likely are, or have been, an issue in some jurisdictions during some phases of the corona crisis, and politicians and health officials should be more transparent about this. Questions that the media should be asking include:

• When did you become aware of the impact of false positives?
• What is the magnitude of the problem currently?
• Have lab testing procedures been modified to address the issue?
• Is wide-spread testing still meaningful at this point in the pandemic?

In fact, just yesterday, the Ontario government changed course by discouraging asymptomatic people from getting tested. Yet this reversal seems more related to preserving lab capacity for symptomatic persons and those with suspected exposure, who need faster test results, than to the fundamental issues with over-testing.

Karina Reiß, Sucharit Bhakdi: Corona Fehlalarm? Zahlen, Daten und Hintergründe [Corona False Alarm? Numbers, Data and Background]. Goldegg, Vienna Austria. Published 1 June 2020 (eBook, EAN 9783990601907) and 23 June 2020 (paperback, 160 pages, ISBN: 978-3-99060-191-4)

Published in the midst of the SARS-CoV-2 pandemic, „Corona Fehlalarm?“ (German for “Corona False Alarm?”) gives reason for deep reflection on where humanity stands with respect to rational decision-making, public health, and the social contract. In fact, the authors would argue that we are in a panic rather than a pandemic, and that we are not in the midst but at the end of the COVID-19 curve, though we may only be at the beginning of much worse collateral damage inflicted by the global overreaction to the appearance of the novel coronavirus in December 2019.

Professor Karina Reiß, whose natural sciences doctorate is in cell biology, is a faculty member in the Department of Dermatology and Allergology at the University Hospital of the northern German province of Schleswig-Holstein in Kiel. Her co-author and husband, retired professor Sucharit Bhakdi, holds a medical doctorate and spent his career as a faculty member in institutes for Medical Microbiology at the universities of Gießen and Mainz in Germany. Dr. Bhakdi has been one of the early critics of the lockdown measures in Germany. On March 26, he publicly asked German Chancellor Dr. Angela Merkel five questions around the threat assessment of COVID-19, which remained unanswered. In a June 3 video interview with alternative news magazine Rubikon, Dr. Bhakdi explained the genesis of the book “Corona False Alarm?” out of his and his wife’s frustration with the repeated extension of many emergency measures by the German governments.

The book consists of ten chapters framed by an introduction and conclusion. The introduction, subtitled “Start of a Nightmare?”, outlines the first half of 2020 that most of us have experienced as an onslaught of bad news and terrifying images from Wuhan’s hospitals to northern Italy’s morgues, supermarket lineups and empty shelves, isolated seniors trapped in long-term care homes and police drones surveying deserted city streets and parks. The authors briefly outline the discovery of the novel coronavirus SARS-CoV-2 and the associated illness COVID-19. Subsequent chapters discuss the data and state of scientific knowledge concerning the public health threat from SARS-CoV-2; describe the pandemic situation in Germany; explain collateral damage from the lockdown measures; and compare the lockdown with Sweden’s light-handed response. Additional chapters suggest alternative emergency measures that could have been taken and analyze the role of the media in this crisis situation. The book ends with a short chapter asking where we will go from here, a concluding note, and an appendix with 208 numbered online references.

The first substantial chapter analyses the threat level of the so-called “killer virus” based on the relation of fatalities to infections. The authors explain three tremendous challenges with counting infections: (1) use of the non-validated PCR test with unknown false-positive and false-negative rates, which becomes problematic when the (true) prevalence of the infection decreases towards the end of an epidemic; (2) testing being limited to symptomatic patients instead of sampling across the entire population from an early stage; and (3) lack of attention to the fact that the number of tests completed directly influences the number of infections found, potentially resulting in a “lab pandemic”. The authors only present a hypothetical example here; I believe they could have easily used the example of Germany or any other country, in which the number of tests conducted were increased significantly as lab capacities became available in the early stages of the corona crisis, resulting in an apparent exponential growth of cases while the percent of positive test results quickly started to decline.

With respect to COVID-19 fatalities, Drs. Reiß and Bhakdi emphasize that the official guidelines in Germany, the UK, Sweden, the US, and probably most other countries are known to count anyone as a “corona death” who has tested positive for the virus, regardless of the ultimate cause of death. In some countries, a suspected infection was enough to be included in the death count. In addition, the agencies discouraged or prohibited autopsies for fear of endangering the pathologist. Nevertheless, a dissenting pathologist in Hamburg conducted autopsies on over 100 corona-related fatalities and found that all of them had at least one co-morbidity, most frequently cardio-vascular diseases. Similar observations are reported from Switzerland and Italy, casting doubt on the degree to which the SARS-CoV-2 virus caused the patients’ death. In this context, the authors place the “corona deaths” in context with Germany’s regular mortality of 2,500 to 3,000 deaths per day, and specifically with the death rate among people over 80 years. The text and graphic are a bit confusing here, but they nevertheless illustrate the minimal impact of COVID-19 even on elderly mortality compared to the big killers: heart disease and cancer.

Still in the same chapter, Drs. Reiβ and Bhakdi summarize different ways to compare the risks from COVID-19 and influenza. The infection-fatality rate (IFR) of a normal flu season in Germany is 0.1% to 0.2% with a few hundred deaths. However, in 2017/18, 25,000 patients died from the flu with 330,000 reported cases, resulting in a stunning 8% lethality. Even the original WHO estimate of 3% to 4% IFR for COVID-19 was lower, while current estimates were revised to 0.4% or less, taking into account a large number of undetected infections. For example, the CDC’s best estimate is now 0.26%, identical to the estimate from a comprehensive population-wide study by Prof. Streeck and team of the corona hotspot Heinsberg county in western Germany. Our book authors emphasize that this makes COVID-19 comparable to a moderate flu season and dispels the myth of the “killer virus”. They also note that while elderly are at much higher risk than the young, it is the co-morbidities that cause death and that many healthy elderly have survived the infection.

This chapter ends with a selective review of local factors that may have influenced the higher death counts and rates in COVID-19 hotspots in Italy, Spain, Britain, and the US. These factors include different testing regimes, historic underfunding of the hospital and healthcare system, hospital infections, antibiotics resistance, ad-hoc guidelines for medical treatment of COVID-19, classification of fatalities, local funeral logistics, fear and panic generated by media images, age structure, and regional air pollution.

Chapter 3 of “Corona False Alarm?” is a sharp critique of the prevailing expert advice and political decisions in Germany, yet it provides many lessons for other countries. The authors denounce the ever-changing goalposts for the pandemic threat assessment, from the case-doubling rate to the effective reproduction number R, the calculation of which changed several times, to thresholds on regional counts of new infections per 100,000 population currently in place. An extensive quote by Stanford Professor John Ioannidis is presented in contrast to the seemingly erratic government communications and decisions around mid-March 2020. Fear-mongering with spurious models, best known from the Imperial College group around Prof. Ferguson, and individual narratives by Germany’s “top” virologist Prof. Drosten about exploding cases and triage decisions in an overburdened healthcase system inevitably led to the lockdown decision effective March 23. Among other evidence that the lockdown was ill-advised, the authors present a copy of the infectious disease agency RKI’s estimated R curve, published mid-April, that shows that the peak of the pandemic was passed in early March before any measures were taken.

Readers with a critical disposition will already know many of these and the following details, but seeing them organized and summarized in book form gives them additional logic and credibility. The RKI’s R curve was extensively scrutinized by Prof. Homburg of the University of Hannover. Another early warning that the pandemic was “over” in late March came from Dr. Wittkowski, whose testimonials could be added to the book. Despite the evidence, the German lockdown was extended and makeshift face-coverings required in some indoor settings such as stores, a move the authors decry as capricious at best. Brainwashing through the mainstream media and the stoking of fear of a “second wave” by Prof. Drosten and others resulted in broad compliance with the lockdown, distancing, and mask regulations. This contrasts with the known seasonality of coronaviruses, illustrated in the book with reference to a 1998 study from Finland. The authors’ frustration is tangible when they report the slow pace of re-opening throughout May and the further extension of many measures until the end of June, and Chancellor Merkel’s recent statements that “we are still at the beginning of the pandemic” …  

In Chapter 4, the German healthcare system and the occupancy of intensive-care beds and respirators throughout the pandemic are discussed. With reference to official data and a model from the “Corona Initiative of German SMEs”, the authors show that the system was nowhere near capacity at any point in time. In addition, they criticize the practice of bringing frail elderly patients, who would have gone into palliative care during normal times, into ICU and expose them to futile respirator treatment. The chapter ends with a summative assessment of the COVID-19 situation in Germany, including that there has never been an exponential growth of infections to begin with, that government decision-makers declared a pandemic emergency without justification and enforced nonsensical measures instead of living up to their oath of office: to work towards the wellbeing of Germans and protect them from harm. A section on “what the government did right” is left demonstratively empty.

Chapter 5 deals with the collateral damage from the lockdown measures. Reference is made to a leaked crisis management analysis from the German Ministry of the Interior, which suggests that the pandemic may have been a global false alarm and its “cure” comes with a disproportionate cost of lives (e.g. from deferred surgeries and stroke sufferers avoiding hospitals), wellbeing (e.g. loneliness, depression, violence, abuse), and prosperity (e.g. unemployment, bankruptcies). A particularly cruel side effect of the social distancing requirements was the isolation of seniors. The authors also highlight the impact on children and on the poorest regions in the world, before turning their sights in Chapter 6 to a handful of countries that averted general lockdowns. Given that more specific and proven infectious disease control measures existed, it is not surprising that high-density Japan (with little testing), South Korea (with extensive testing and tracing), Hong Kong, Iceland, and even the (in)famous Sweden have similar (or better) epidemic curves and death rates as the countries with the strictest and longest lockdowns, including France, Italy, and Spain. The authors call out German politicians and media for putting illicit pressure on Swedish decision-makers to follow suit with the Europe-wide lockdowns. Since Sweden has now reached one of the higher death rates in the world, it would be helpful to add details that may explain the – in today’s perspective – mixed results of the Swedish approach. Conversely, an interesting example included in the book is the Czech Republic where due to a court decision some restrictions were eased much earlier (late April) than elsewhere, without noticeable impact on COVID-19 cases.

According to Drs. Reiβ and Bhakdi, consistent protection of the at-risk population, in particular the residents of long-term care homes, would have been the right approach to addressing SARS-CoV-2. Chapter 7 also deconstructs politicians’ claims that the pandemic continues and normality will not return “until a vaccine is found”. Lockdown sceptics were particularly dismayed when Bill Gates got to make a 9-minute statement on public TV’s 15-minute prime time news show, decreeing that all 7 billion humans will be immunized with a vaccine developed in a time span compacted from five years to 18 months by skipping some of the required safety checks. Our authors explain immunity to coronaviruses on the basis of two natural mechanisms involving anti-bodies and t-cells, noting that t-cell immunity against coronaviruses has been largely ignored in public discourse. The much cited “herd immunity” for corona and flu viruses is described as a relative concept, which also relies on cross-immunity from earlier virus variants. Existing cross-immunity may very well explain the high percentage of asymptomatic and mild infections with SARS-CoV-2. Importantly, the same virus can never cause a catastrophic second wave, although a new, significantly different variant could. Given these factors, the authors call the aspiration to develop a SARS-CoV-2 vaccine foolish. They note parallels to the 2009 swine flu outbreak and the role of the WHO in determining what constitutes a pandemic. The same government advisors of today warned of a deadly disease then, and recommended the purchase of millions of doses of a quickly developed vaccine, which later had to be destroyed. And some of the same critics raised their voice, including physician and health politician Dr. Wodarg and one of our authors, Prof. Bhakdi, competent voices of reason that again today are ignored by decision-makers.

Chapter 8 turns to one of the most disturbing developments in the corona crisis of 2020: the role of the mainstream media, their journalists, and the censorship of social media and the web. The public broadcasters in Germany and many other European countries are considered the fourth branch of societal power, with a mandate to control the legislative, executive, and judiciary branches. They are legally required to be politically independent and contribute to the formation of public opinion – supposedly by reporting on opposing views regarding major questions and events. The book illustrates the complete failure of Germany’s public broadcasters along with private mainstream media (and parliamentary opposition) to critically monitor government action. The authors outline the fear-mongering on national and regional TV, the uncritical reporting on a limited subset of science and modeling, and the discrediting and silencing of dissenting viewpoints. What should be added here is the emergence of a grassroots democratic resistance movement, whose goal to restore and protect the constitution was equally ignored, if not ridiculed, by the mainstream media.

In addition, internal and external “fact checkers” produced inaccurate ratings that flagged alternative perspectives as conspiracy theories and led to shadow banning or complete removal of YouTube videos and Facebook posts as well as temporary web site closures. Meanwhile, the often changing and contradictory messages from governments and WHO were taken as the only permissible narrative. In interviews, Prof. Bhakdi repeatedly stated that it should not be considered “courageous” in a democracy to state one’s dissenting opinion. Yet, disturbingly, we have indeed reached this point, both with respect to personal opinions vis-à-vis family members, friends, and neighbours as well as regarding expert opinions. The authors of “Corona False Alarm?” take government, opposition, the media, and those in the know – here doctors and scientists – to task and accuse those, who remain silent, of complicity with regards to the collateral damage done.

The book ends with an even darker concluding Chapter 9 and a brief and faintly hopeful summary. The suspension of constitutional freedoms of opinion, speech, movement, assembly, exercise of religion, and choice of profession was not proportional to the public health threat from SARS-CoV-2. Germans should have been particularly vigilant when critical journalism went missing, mass hysteria was stoked, and public opinion constrained to a single narrative. The invitation to snitch on fellow citizens for violations of lockdown regulations is another sign of totalitarian practices established within a few months in what many of us considered a healthy democracy. I concur with Drs. Reiβ and Bhakdi that there will be extensive research and inquiry needed to learn from the corona crisis. The authors express their hope that the book will help prevent that (this!) history ever repeats itself.

Although it must have been put together with a red-hot needle (or keyboard?), the book reads well with a stringent storyline and fitting transitions between chapters. A few inaccuracies, duplications, and omissions are excused by the urgency to publish this important perspective on the ongoing corona crisis. While the information is often specific to German events and actors, some additions could be made to cover the development of the crisis in German-speaking Austria and Switzerland, which had their own distinct experiences. Translations into other languages would likely require some clarifications, if not the addition of regionally relevant contents. Owing to the subject, reading “Corona False Alarm?” could be quite upsetting for the unsuspecting reader, yet it is a must-read for anyone who wants to understand what on earth just happened!