On The Lancet editorial

On May 8, The Lancet published an editorial criticising the Narendra Modi government’s response to India’s second COVID-19 outbreak, which has been redefining the meaning of ‘snafu’. All hell broke loose. Of course, hell has been breaking loose for quite some time in India now, but the latest episode was in one specific sense also gratifying to behold.

There were the usual rumbles in the week following the editorial’s appearance, until on May 17 India’s health minister Dr Harsh Vardhan shared a blog post penned by a Pankaj Chaturvedi deriding The Lancet‘s choice of arguments. (I’m fond of emboldening the honorific: it shows doctors can be stupid, too.) The post is mostly whataboutery studded with a few gems about how people who liked the editorial aren’t pissed enough that favipiravir and hydroxychloroquine were approved for use – as Dr Vardhan’s ministry did. More importantly, it seems Dr Vardhan, and his colleagues in fact, threw themselves into the barrel looking for anything with fully formed sentences that said The Lancet was wrong – a sign that their government still gives a damn about what foreign journals, and perhaps magazines and newspapers too, say about it.

We need to use this to the fullest extent, and I daresay that it’s the sort of resource the government is going to find difficult to duplicate as well. There was recently an article about Modi doing a great job during India’s second wave, published in an outlet called The Daily Guardian. There was enough confusion to draw the UK’s The Guardian forward and clarify that it was an unaffiliated entity – but no amount of confusion can supplant an institution, no matter how illiberal. Aakar Patel wrote in 2018: “The fact is that intelligent and intellectual bigotry is very difficult. There are very few people who can pull that off and that is why we can count the major ones on our fingers.” This is also why the government has twitched every time the New York Times, the Washington Post, BBC, The Lancet, Science and The BMJ have published articles critical of India, even if this isn’t the full picture.

It’s doubly interesting that the sophistry of the rejoinders aside, Dr Vardhan, his colleagues in government and his party’s supporters have all been antagonised by what they perceive to be a political act by a medical journal. This is an untenable distinction, of course – one that fantasises about a clear divide between the Watchers, who look out, and the Watched, who dare not know what the Watchers see. More pertinently, it’s a reflection of what they desperately expect from their own compatriots: to ignore how bad political leadership could help a virus ravage hundreds of thousands of families.

Featured image credit: Kunj Parekh/Unsplash.

Spray and pray – the COVID-19 version

Kiran Mazumdar-Shaw is the head of Biocon, a company headquartered in Bengaluru and which has repurposed a drug called itolizumab – already approved to help manage severe chronic psoriasis in different markets – to manage cytokine release syndrome (CRS) in COVID-19 patients. Setting aside CRS’s relevance in the COVID-19 pathology (considering it is currently in dispute), Mazumdar-Shaw and a specific coterie of Biocon employees have been aggressively marketing itolizumab despite the fact that its phase II clinical trial seems by all accounts to have been a joke. (I recommend this account.)

Funnily enough, The Print published an article by Mazumdar-Shaw on September 1, in which she describes her experience of the infection (she’s one of The Print‘s funders). Two portions of the article are striking. One is the following paragraph about her treatment, which tacitly implicates a host of drugs and devices in her recovery without providing any additional information of their respective usefulness:

Dr Murli Mohan from Narayana Health, Bengaluru and Dr Shashank Joshi from Lilavati hospital, Mumbai, were my key medical supervisors. I was put on a course of Favipiravir, azithromycin and paracetamol. Apart from this, I continued with my daily dose of Vitamin C, Vitamin D, Zinc, baby aspirin and chyavanprash. Not to mention my twice a week 200mg dose of HCQ. Day two and three were uneventful. I was measuring my oxygen saturation levels six times a day, which were all between 96-98 per cent even after a brisk six-minute walk. My temperature was normal but late evening on Day three, I felt fluish and it extended to Day four and five. No measurable temperature but frequent bouts of sweating, which suggested that my body was fighting the virus. I was also tracking my Cytokine levels.

Reading this brought to mind a terrible period in early 2010, when I had malaria and jaundice together with an unusually strong spate of migraines. I can’t remember the exact drugs and diet that got me feeling better. But after reading what Mazumdar-Shaw went through, I’m inclined to attribute my recovery also to the mug of Bournvita I had every night before bed.

The other striking portion is a list of suggestions that subtly make the case to pay more attention to CRS and treat it with the drugs available in the market for it: “Doctors should not just treat clinical symptoms but rather the cause of the symptoms. If SpO2 (oxygen saturation) reduces, just increasing oxygen flow is not the answer. Treating inflammation caused by cytokines is the answer.” Wonder why researchers don’t yet have consensus… But the Drug Controller General of India has approved two drugs to treat CRS due to COVID-19 in India (through a highly criticised approval process) – and Kiran Mazudar-Shaw’s Biocon’s itolizumab is one of them.

The list is also prefaced by the following statement, among others: “… avoid TV and social media as negative news is bad for fighting Covid-19.” I wonder if this refers to criticism against hydroxychloroquine (HCQ), favipiravir, azithromycin and purported Ayurvedic remedies as well.

India’s missing research papers

If you’re looking for a quantification (although you shouldn’t) of the extent to which science is being conducted by press releases in India at the moment, consider the following list of studies. The papers for none of them have been published – as preprints or ‘post-prints’ – even as the people behind them, including many government officials and corporate honchos, have issued press releases about the respective findings, which some sections of the media have publicised without question and which have quite likely gone on to inform government decisions about suitable control and mitigation strategies. The collective danger of this failure is only amplified by a deafening silence from many quarters, especially from the wider community of doctors and medical researchers – almost as if it’s normal to conduct studies and publish press releases in a hurry and take an inordinate amount of time upload a preprint manuscript or conduct peer review, instead of the other way around. By the way, did you know India has three science academies?

  1. ICMR’s first seroprevalence survey (99% sure it isn’t out yet, but if I’m wrong, please let me know and link me to the paper?)
  2. Mumbai’s TIFR-NITI seroprevalence survey (100% sure. I asked TIFR when they plan to upload the paper, they said: “We are bound by BMC rules with respect to sharing data and hence we cannot give the raw data to anyone at least [until] we publish the paper. We will upload the preprint version soon.”)
  3. Biocon’s phase II Itolizumab trial (100% sure. More about irregularities here.)
  4. Delhi’s first seroprevalence survey (95% sure. Vinod Paul of NITI Aayog discussed the results but no paper has pinged my radar.)
  5. Delhi’s second seroprevalence survey (100% sure. Indian Express reported on August 8 that it has just wrapped up and the results will be available in 10 days. It didn’t mention a paper, however.)
  6. Bharat Biotech’s COVAXIN preclinical trials (90% sure)
  7. Papers of well-designed, well-powered studies establishing that HCQ, remdesivir, favipiravir and tocilizumab are efficacious against COVID-19 🙂

Aside from this, there have been many disease-transmission models whose results have been played up without discussing the specifics as well as numerous claims about transmission dynamics that have been largely inseparable from the steady stream of pseudoscience, obfuscation and carelessness. In one particularly egregious case, the Indian Council of Medical Research announced in a press release in May that Ahmedabad-based Zydus Cadila had manufactured an ELISA test kit for COVID-19 for ICMR’s use that was 100% specific and 98% sensitive. However, the paper describing the kit’s validation, published later, said it was 97.9% specific and 92.37% sensitive. If you know what these numbers mean, you’ll also know what a big difference this is, between the press release and the paper. After an investigation by Priyanka Pulla followed by multiple questions to different government officials, ICMR admitted it had made a booboo in the press release. I think this is a fair representation of how much the methods of science – which bridge first principles with the results – matter in India during the pandemic.

A non-self-correcting science

While I’m all for a bit of triumphalism when some component of conventional publication vis-à-vis scientific research – like pre-publication anonymous peer review – fails, and fails publicly, I spotted an article in The Conversation earlier today that I thought crossed a line (and not in the way you think). In this article, headlined ‘Retractions and controversies over coronavirus research show that the process of science is working as it should’, the author writes:

Some people are viewing the retractions [by The Lancet and the New England Journal of Medicine] as an indictment of the scientific process. Certainly, the overturning of these papers is bad news, and there is plenty of blame to go around. But despite these short-term setbacks, the scrutiny and subsequent correction of the papers actually show that science is working. Reporting of the pandemic is allowing people to see, many for the first time, the messy business of scientific progress.

The retraction of the hydroxychloroquine paper … drew immediate attention not only because it placed science in a bad light, but also because President Trump had touted the drug as an effective treatment for COVID-19 despite the lack of strong evidence. Responses in the media were harsh. … [Their] headlines may have [had] merit, but perspective is also needed. Retractions are rare – only about 0.04% of published papers are withdrawn – but scrutiny, update and correction are common. It is how science is supposed to work, and it is happening in all areas of research relating to SARS-CoV-2.

If you ask me, this is not science working as it should. This is the journals that published the papers discovering that the mechanisms they’d adopted that they’d said would filter fraudulent papers letting fraudulent papers slip through.

But by the author’s logic, “this is science working as it should” would encompass any mistake that’s later discovered, followed by suitable corrective action. This is neither here nor there – and more importantly it allows broken processes to be subsumed under the logic’s all-encompassing benevolence. If this is scientific publishing as it should be, we wouldn’t have to think deeply about how we can fix anonymous pre-publication peer-review because it wouldn’t be broken. However, we know in reality that it is.

If anything, by advancing his argument, the author has cleverly pressed an argumentative tack that supporters of more progressive scientific publishing models in the service of preserving the status quo. Instead, we need to acknowledge that an important part of science, called science publishing, has evolved into a flawed creature – so that we can set about bending the moral arc towards fixing it. (We already know that if we don’t acknowledge it, we won’t fix it.)

The costs of correction

I was slightly disappointed to read a report in the New York Times this morning. Entitled ‘Two Huge COVID-19 Studies Are Retracted After Scientists Sound Alarms’, it discussed the implications of two large studies of COVID-19 recently being retracted by two leading medical journals they were published in, the New England Journal of Medicine and The Lancet. My sentiment stemmed from the following paragraph and some after:

I don’t know if just these two retractions raise troubling questions as if these questions weren’t already being asked well before these incidents. The suggestion that the lack of peer-review, or any form of peer-review at all in its current form (opaque, unpaid) could be to blame is more frustrating, as is the article’s own focus on the quality of the databases used in the two studies instead of the overarching issue. Perhaps this is yet another manifestation of the NYT’s crisis under Trump? 😀

One of the benefits of the preprint publishing system is that peer-review is substituted with ‘open review’. And one of the purposes of preprints is that the authors of a study can collect feedback and suggestions before publishing in a peer-reviewed journal instead of accruing a significant correction cost post-publication, in the form of corrections or retractions, both of which continue to carry a considerable amount of stigma. So as such, the preprints mode ensures a more complete, a more thoroughly reviewed manuscript enters the peer-review system instead of vesting the entire burden of fact-checking and reviewing a paper on a small group of experts whose names and suggestions most journals don’t reveal, and who are generally unpaid for their time and efforts.

In turn, the state of scientific research is fine. It would simply be even better if we reduced the costs associated with correcting the scientific record instead of heaping more penalties on that one moment, as the conventional system of publishing does. ‘Conventional – which in this sphere seems to be another word for ‘closed-off’ – journals also have an incentive to refuse to publish corrections or perform retractions because they’ve built themselves up on claims of being discerning, thorough and reliable. So retractions are a black mark on their record. Elisabeth Bik has often noted how long journals take to even acknowledge entirely legitimate complaints about papers they’ve published, presumably for this reason.

There really shouldn’t be any debate on which system is better – but sadly there is.

A caveat for peer-review

Now that more researchers are finding more holes in the study in The Lancet, which claimed hydroxychloroquine – far from being a saviour of people with COVID-19 – actually harms them, I wonder where the people are who’ve been hollering that preprint servers be shut down because they harm people during a pandemic.

The Lancet study, entitled ‘Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis’, was published online on May 22, 2020. Quoting from the section on its findings:

After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group, hydroxychloroquine, hydroxychloroquine with a macrolide, chloroquine, and chloroquine with a macrolide were each independently associated with an increased risk of in-hospital mortality. Compared with the control group, hydroxychloroquine, hydroxychloroquine with a macrolide, chloroquine, and chloroquine with a macrolide were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

I assume it was peer-reviewed. According to the journal’s website, there is an option for researchers to have their submission fast-tracked if they’re so eligible (emphasis added):

All randomised controlled trials are eligible for Swift+, our fastest route to publication. Our editors will provide a decision within 10 working days; if sent for review this will include full peer review. If accepted, publication online will occur within another 10 working days (10+10). For research papers, which will usually be randomised controlled trials, judged eligible for consideration by the journal’s staff will be peer-reviewed within 72 h and, if accepted, published within 4 weeks of receipt.

The statistician Andrew Gelman featured two critiques on his blog, both by a James Watson, on May 24 and May 25. There are many others, including from other researchers, but these two provide a good indication of the extent to and ways in which the results could be wrong. On May 24:

… seeing such huge effects really suggests that some very big confounders have not been properly adjusted for. What’s interesting is that the New England Journal of Medicine published a very similar study a few weeks ago where they saw no effect on mortality. Guess what, they had much more detailed data on patient severity. One thing that the authors of the Lancet paper didn’t do, which they could have done: If HCQ/CQ is killing people, you would expect a dose (mg/kg) effect. There is very large variation in the doses that the hospitals are giving … . Our group has already shown that in chloroquine self-poisoning, death is highly predictable from dose. No dose effect would suggest it’s mostly confounding. In short, it’s a pretty poor dataset and the results, if interpreted literally, could massively damage ongoing randomised trials of HCQ/CQ.

On May 25:

The study only has four authors, which is weird for a global study in 96,000 patients (and no acknowledgements at the end of the paper). Studies like this in medicine usually would have 50-100 authors (often in some kind of collaborative group). The data come from the “Surgical Outcomes Collaborative”, which is in fact a company. The CEO (Sapan Desai) is the second author. One of the comments on the blog post is “I was surprised to see that the data have not been analysed using a hierarchical model”. But not only do they not use hierarchical modelling and they do not appear to be adjusting by hospital/country, they also give almost no information about the different hospitals: which countries (just continent level), how the treated vs not treated are distributed across hospitals, etc.

(Gelman notes in a postscript that “we know from experience that The Lancet can make mistakes. Peer review is nothing at all compared to open review.” – So I’m confident the study’s paper was peer-reviewed before it was published.)

Perhaps it’s time we attached a caveat to claims drawn from peer-reviewed papers: that “the results have been peer-reviewed but that doesn’t have to mean they’re right”, just as journalists are already expected to note that “preprint papers haven’t been peer-reviewed yet”.

‘Science alone triumphs’: A skeptic annotates

An article entitled ‘Science alone triumphs: Providing a true picture of the world, only science can help India against coronavirus’, penned by a Jayant Sinha, appeared on the Times of India‘s editorials page on April 8, 2020. My annotated reading of the article follows…

As the coronavirus continues its deadly spread around the world, it is only science that protects us. Many different scientists and experts are responding to the global challenge…

A sweeping statement that suggests whatever science can protect for us are the only things worth protecting. Obvious exceptions include social security, access to food and other essential supplies, protection against discrimination and stigma, and of course individual rights. The author quite likely does not intend to imply that one’s biological safety is more important than any of these other attributes, but that’s what the words imply.

… Their deep technical expertise, honed through years of education and practice, keeps us from falling into the abyss.

A bit too florid but okay.

Ultimately, it is the practice of science – developing new ideas, testing them against hard evidence, replicating them successfully, scaling them up, and then further improving them through honest feedback – that drives all of them.

It’s quite heartening to have a lawmaker acknowledge these aspects of the scientific method, esp. a member of the Bharatiya Janata Party, but these exact are also curious at this time. The Indian Council of Medical Research has allowed frontline health workers to consume hydroxychloroquine as a prophylactic against COVID-19 with flimsy (if that) evidence to support the drug’s efficacy and safety. Where are the tests, leave alone the replication studies?

This is the quintessential scientific method, the unrelenting search for truth.

More than 99% of the article’s readers are unlikely to notice a difference between the scientific method and the search for truths (I prefer using the plural), but it exists: the scientific method is a way to acquire new knowledge about the natural universe. The nature of the quest depends on the practitioner – the scientist.

What science tells us about coronavirus infections has reached everyone. People are wearing masks, washing their hands, and avoiding crowds. Yet most people I meet are stumped by questions such as: What is a virus? How does it actually spread? How does your body fight the coronavirus? Why do some people die from the virus? This indeed is the great paradox of our times.

Truly!

Even as science becomes more vital, fewer and fewer people understand and appreciate it. As a child who loved science, as a young man trained in engineering, and as a technocrat who believes in analytical reasoning and hard evidence, I find this hard to accept.

I’m not sure if the author means he does not understand why this paradoxical engagement with science persists but I have some ideas:

  1. Science is becoming increasingly more specialised, and a lot of what we learn from the cutting edge these days cannot be communicated to anyone without at least 18 years of education.
  2. Most people think they understand science when they really mean they’re familiar with its commonest precepts and scientists’ pronouncements. Their knowledge is still only based on faith: that, for example, the new coronavirus spreads rapidly but not why so, freeing them to use scientific knowledge in unscientific narratives.

(Reason: because the virus’s spike proteins have evolved to establish stronger bonds with the ACE2 receptor protein produced by cells in the respiratory tract, compared to the spike proteins of the closely related SARS virus, as well as the ability to attach, albeit less strongly, to another protein – furin – produced by all cells in the body.)

To change this state of affairs, we must focus on four key areas. … We are afflicted by too much quackery and superstition.

Is this article really a dog-whistle? The author is the BJP MP from Hazaribagh (Jharkhand) so there is some comfort – no matter how fleeting – that the BJP is not completely devoid of appreciation for science. However, I’m curious how often the author has brought these issues up with other BJP lawmakers, including the prime minister himself, who have frequently issued a stream of nonsense that undermines a scientific understanding of the world. The answer wouldn’t affect what we should or shouldn’t take away from this piece, but this not uncommon practice of speaking sense in some fora but shutting up in others is annoying, especially when the speaker wields some power.

… Of course, mythology has immense power to shape people’s beliefs, but it must be acknowledged that it is only science that can solve our material problems.

Well said… I think. Can’t be a 100% sure.

While there is certainly much wisdom in age-old practices, it is primarily because there is a genuine scientifically proven cause-and-effect relationship that underlies these practices.

No. Specifically, causality – nor any of the properties we associate with modern science – is not a precondition for traditional wisdom, beliefs and rituals, nor is it meaningful to attempt to validate such wisdom, beliefs and rituals using filters developed to qualify scientific theories of the natural universe. Science and tradition (in many contexts) are born of and seek to fulfil different purposes. Additionally, science alone does not empower – traditional practices do as well (look no further than tribal groups that have been stewarding many of India’s forests for centuries) – and science abandoned by the guiding hand of social forces has often become an instrument of disempowerment.

… In short, we would all be much better off if we shifted some of our time and resources away from blind faith and towards a better scientific understanding of the world.

This is very true. Faith has its place in the world (more so than some might like to acknowledge); outside this finite domain, however, it’s a threat.

Second, our children must learn honestly about science. There is no ‘Western’ concept of science taught in schools which should then be negated at home. Science is universal – just look up the path-breaking research conducted by SN Bose, or CV Raman, or S Chandrasekhar. The pure scientific truth that they discovered holds true everywhere, even in the deep cosmos.

💯 A diversity in the choice of names (by gender or by caste, for example) would have been better.

Teachers and parents must tell children that science is the pursuit of truth and provides a true picture of the world.

As the children grow up, can we encourage our teachers and parents to communicate more nuanced ideas of what science is and why it was invented?

… We should not demand obedience from our children, rather we should encourage them to probe all that we do. …

Again, is this article really a dog-whistle?

Third, we must revere our scientists and technologists.

Never revere another human. Never assume anyone is closed off to (constructive) criticism, particularly when they deserve it. Obviously there’s a time and place (including absurd advice like “don’t berate a surgeon in the middle of a surgery”), but when such opportunities arise don’t let reverence stop you.

It is through their efforts that we flourish today.

Brian Josephson won the Nobel Prize for physics in 1973 for predicting the Josephson effect but he also supported the “water memory” hypothesis that claimed to make sense of homeopathic remedies. Giving scientists the keys to running the world is not guaranteed to produce the desired results.

… Even our start-up culture tends to value the business celebrity, not so much the tech nerd. …

The author is probably thinking of celebrity tech nerds, the Bezoses and the Jobses. “Nerds” and “geeks” in general have become more popular and their culture more socially and commercially profitable.

Billions of dollars of wealth has been created by writing great code, developing insanely good products, creating clever new financial solutions, and establishing entirely new scientific approaches. …

Many of these “insanely good products” have also progressively eroded democracy. To quote Jacob Silverman in The Baffler (at length, hoping Silverman doesn’t mind):

The fundamental underlying problem is the system of economic exchange we’re dealing with, which is sometimes called surveillance capitalism. It’s surveillance capitalism that, by tracking and monetizing the basic informational content of our lives, has fueled the spectacular growth of social media and other networked services in the last fifteen years. Personal privacy has been annihilated, and power and money have concentrated in the hands of whoever owns the most sophisticated machine to collect and parse consumer data. Because of the logic of network effects—according to which services increase in value and utility as more people use them—a few strong players have consolidated their control over the digital economy and show little sign of surrendering it.

It wasn’t supposed to be this way. For years, tech executives and data scientists maintained the pose that a digital economy run almost exclusively on the parsing of personal data and sensitive information would not only be competitive and fair but would somehow lead to a more democratic society. Just let Facebook and Google, along with untold other players large and small, tap into the drip-drip of personal data following you around the internet, and in return you’ll get free personalized services and—through an alchemy that has never been adequately explained—a more democratized public sphere.

While these promises provided the ideological ballast for the tech revolution of the last decade or two, they turned out to be horribly wrong. There is nothing neutral, much less emancipatory, about our technological systems or the data sloshing through them. They record and shape the world in powerful, troubling ways. The recent clutch of stories, including in the New York Times and the Guardian, about Cambridge Analytica, the favored data firm of the Trump campaign, provides a humbling example of how personal data can be used to manipulate voter populations. This essential truth has been known at least since 2012, when a University of California-San Diego study found that a few nudges on Facebook appreciably increased voter turnout. From there, it’s only a small jump to isolating and bombarding millions of potential Trump voters with customized appeals, as Cambridge Analytica did.

In the final analysis, the author’s association of “scientific approaches” with technological triumphalism is just a very good reminder that “scientific approaches” don’t have morals built-in.

Finally, we must massively strengthen our scientific institutions. … The hard work of science gets done in these places and they must be among the best in the world.

Without specifying how ‘best’ or even ‘better’ needs to be measured, the task of strengthening institutes is at risk of being hijacked by the single-minded pursuit of better scores on ranking tables.

… Our best diaspora scientists should be provided generous support to come back to India and set up their research labs. Top scientific institutions must be granted the autonomy to govern themselves, hire the best faculty, attract great students from around the world, and pursue the best research. …

I once picked a fight with a scientist after he submitted a piece arguing that the Government of India should improve the supply of masks and other PPE to tame India’s tuberculosis burden. He couldn’t understand why I was opposed to publishing the piece, insisting he was “saying the rights things – the things that need to be said.” Here’s the thing: no one disagrees, and the dialogue has in fact moved leaps and bounds ahead. So while it may be the right thing to say, I’m not sure it needs to be said – much less deserves a thousand words. Put differently: You’re a minister, try moving the needle!

To that end, I have introduced a private members bill to grant IIM-level autonomy to the IITs that have been selected as institutions of eminence.

Okay… Is this what the article was about: to build support for your Bill? According to PRS, fewer than 4% of private members’ Bills were even discussed during the 14th Lok Sabha (i.e. Modi’s first term as prime minister). Why not build support within the party and introduce it as a government Bill?

Our civilisation is marked by its unending quest for knowledge, … The Mundaka Upanishad enlightens us: Satyameva Jayate – Truth alone triumphs. Our republic is based on this eternal principle.

Seriously, STAHP. 😂