Whistleblowing is Hard (and Dangerous): Theranos Edition

Just drop everything and read this absolutely gripping WSJ story on Tyler Shultz, the Theranos whistleblower (who also happens to be the grandson of former Secretary of State George Shultz, who was -- and continues to be -- associated with Theranos).

This snippet is from the section where the lawyers appear:

A few weeks later, Mr. [Tyler] Shultz was confronted by his father after arriving for dinner with his parents at their home in Los Gatos, Calif. His grandfather had called to say Theranos suspected he had talked to the Journal reporter. Theranos’s lawyers wanted to meet with him the next day.

He says he called his grandfather and asked if they could meet without lawyers. The elder Mr. Shultz agreed and invited his grandson to his house. The mood was tense but cordial, Tyler Shultz recalls, and he denied talking to any reporters. He says his step-grandmother was present during the conversation.

His grandfather asked if he would sign a one-page confidentiality agreement to give Theranos peace of mind. According to Tyler Shultz, when he said yes, his grandfather revealed that two lawyers were waiting upstairs with the agreement.

Anant Bhan on Gender Gap in Medical Education Leadership in India

Anant Bhan has a link-filled post over at British Medical Journal Blogs:

Given the high number of women entering medicine—a status report in 2012 pegged the number of female medical students in India at around 200 000, compared with 175 000 male students—and subsequently also joining as faculty in medical colleges, one would expect a significant number of them to occupy top leadership positions in medical education. This is where there seems to be a gap—much fewer women occupy positions of director or principal in medical colleges in India than men.

Let’s take the example of those institutes of national importance in India which offer medical education courses. There are 11 of them: the seven All India Institutes of Medical Science (AIIMS; in Delhi, Rishikesh, Jodhpur, Bhopal, Raipur, Patna, Bhubaneshwar), the Postgraduate Institute of Medical Education and Research (PGIMER, Chandigarh), the Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER, Puducherry), the National Institute of Mental Health and Neuroscience (NIMHANS, Bengaluru), and the Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST, Thiruvananthapuram). Of these 11 institutions, currently only one has a female director—Asha Kishore became the first female director of SCTIMST in mid-July 2015 after the institute had been without a director for two years.

Links

1. Ben Goldacre in Buzzfeed News: Scientists Are Hoarding Data And It’s Ruining Medical Research. "Major flaws in two massive trials of deworming pills show the importance of sharing data — which most scientists don’t do."

2. Hari Pulakkat in Economic Times Blogs: Why India is lagging in disruptive innovation.

3. John P.A. Ioannidis in Al Jazeera: Could Greece become prosperous again?

   Populism and a critical lack of know-how is the common denominator among the neo-Stalinist syndicalists, outspoken nationalists and eccentric university professors (most of whom are entirely disconnected from serious global scholarship) who now happen to run the country. Mass media, justifiably anxious to create anti-austerity heroes, manufactured an artificial reality about these people. For example, the original finance minister, Yanis Varoufakis, was heralded as a famous professor of economics, while he has never authored a single scientific article in any of the 30 top economics journals (as ranked based on citation impact factor by Thomson Reuters). In education and science, the two fields where Greeks particularly excel, emerging state policies are strikingly counterproductive. In his inaugural parliament speech, the minister of education (a professor emeritus) proudly declared himself a Marxist who considers excellence a stigma; fittingly, his deputy minister, a university professor of genetics, has not published any PubMed-indexed peer-reviewed scientific paper since 1996. This is Greek mediocrity at its finest.

Problems at AIIMS

While the present government has chosen to continue with the UPA regime's policy of opening new AIIMS in different states, how well has the original AIIMS at Delhi been functioning? M. Rajshekhar has a two-part   series in The Economic Times on this very question. Here's an excerpt from the second part from a section on the governance structure of AIIMS, and how the Health Minister's leadership of the board poses problems:

Corruption and nepotism

A handful of India's public health institutions are deeply respected across India. There is AIIMS, Post Graduate Institute of Medical Education and Research (PGI) Chandigarh, National Institute of Mental Health and Neuro Sciences, Bengaluru, and Jawaharlal Institute of Postgraduate Medical Education and Research (Jipmer), Pondicherry.

Of these, AIIMS stands out in one important way. Says a former health secretary: "There is greater political interference in AIIMS than in other colleges like Nimhans or Jipmer. It is almost a tradition that the health minister will be the chairman of AIIMS."

An MP on the board of AIIMS, who spoke to ET on condition of anonymity, said the minister outranks everyone else on the AIIMS board. As per the AIIMS Act, the governing board should have the DG (health services), representatives from the ministries of health and finance, four medical scientists, one "non-medical scientist" and three MPs. "In this board," said the MP, "everyone is at the same level — below the minister. So what he says goes."

Should the health minister also be AIIMS' chairman? Does this indeed leave AIIMS autonomous? "It's a position with a lot of prestige and power. They can oblige people by getting them admitted into the hospital," says the health ministry ex-CVO.

Links

1. Must-read essay of the week: Stephen Marche in The Guardian: Centireading force: why reading a book 100 times is a great idea. Brought back wonderful memories of reading Tamil writer Sujatha's novels so many, so many times that Marche's description of this experience totally resonated with me: "familiarity with the text verges on memorisation – the sensation of the words passing over the eyes like cud through the fourth stomach of a cow." He actually has more about this experience:

   By the time you read something more than a hundred times, you’ve passed well beyond “knowing how it turns out”. The next sentence is known before the sentence you’re reading is finished. As I reread Hamlet now, I know as Gertrude says, “Why seems it so with thee?” that Hamlet will say “Seems, Madam? Nay it is. I know not seems.” I know as Bertie asks “What are the chances of a cobra biting Harold, Jeeves?” that Jeeves will answer: “Slight, I should imagine, sir. And in such an event, knowing the boy as intimately as I do, my anxiety would be entirely for the snake.” Centireading reveals a pleasure peculiar to text lurking underneath story and language and even understanding.

2. Austin Frakt and Aaron E. Carroll in NYTimes: Can This Treatment Help Me? There’s a Statistic for That. And that statistic is called NNT -- number needed to treat:

   Developed in the 1980s, the N.N.T. tells us how many people must be treated for one person to derive benefit. An N.N.T. of one would mean every person treated improves and every person not treated fails to, which is how we tend to think most therapies work.

   What may surprise you is that N.N.T.s are often much higher than one. Double- and even triple-digit N.N.T.s are common.

   [Take the case of aspirin, for example.] According to clinical trials, if about 2,000 people follow these guidelines over a two-year period, one additional first heart attack will be prevented.

   That doesn’t mean the 1,999 other people have heart attacks. The fact is, on average about 3.6 of them would have a first heart attack regardless of whether they took the aspirin. Even more important, 1,995.4 people would never have a heart attack whether or not they took aspirin. Only one person is actually affected by aspirin. If he takes it, the number of people who remain heart attack-free rises to 1996.4. If he doesn’t, the number remains 1995.4. But for 1,999 of the 2,000 people, aspirin doesn’t make any difference at all.

3. Evelyn Lamb in SciAm Blogs: Gauss and Germain on Pleasure and Passion. Excerpts from a wonderful letter from Carl Friedrich Gauss to Sophie Germain after he learnt that Germain, who was writing to him earlier under the name of one Monsieur LeBlanc, was actually a woman.

Measuring the effectiveness of medication

Sarah Fallon at Wired has an informative story on putting a number, called the number needed to treat (NNT), on the effectiveness of medication and procedures.

Developed by a trio of epidemiologists back in the ’80s, the NNT describes how many people would need to take a drug for one person to benefit. [...] If your kid is throwing up and you take her to the hospital, she might get a drug called Zofran. The NNT for that is 5, meaning that only five kids need to take Zofran for one of them to stop throwing up.

The story goes on to talk about a site called TheNNT.com with the tagline, "Quick summaries of evidence-based medicine."

It’s unfortunate ... that the NNT is not a statistic that’s routinely conveyed to either doctors or patients. But you can look it up on a site that you’ve probably never heard of: TheNNT.com. Started by David Newman, a director of clinical research at Icahn School of Medicine at Mount Sinai hospital, the site’s dozens of contributors analyze the available studies, crunch the numbers on benefits and harms, and then post the results.

Here's a bit more on NNT and how it is assigned to a medication or a treatment procedure:

As statistical tools go, the idea of the number needed to treat is relatively new. It was first described in 1988 by epidemiologists Andreas Laupacis, David Sackett, and Robin Roberts in a New England Journal of Medicine article titled “An Assessment of Clinically Useful Measures of the Consequences of Treatment.” They start by sketching out the problems with a number called the relative risk reduction. That’s the measure you often see hyped in media reports of scientific studies. Imagine, for example, a study of heart disease that finds that a new drug reduces the risk of death by an astonishing 50 percent. The reality behind that number is that the risk of death over a 10-year period for, say, a healthy 45-year-old man weighing 200 pounds went from 5 percent to 2.5 percent—50 percent! Such a finding is clinically significant, yes. Worthy of publication, maybe. But not quite as astonishing.

It would be better, the authors write, to look at a number called the absolute risk reduction—the 2.5 percent reduction that resulted from the new drug. But working with that measure can be hard to understand, because it is actually a percent of a percent. To make it more intuitive and apprehendable, the authors explain, you can use the inverse of absolute risk reduction: Divide 1 by 2.5 percent, or .025, to get 40. And that’s the number needed to treat. Forty people have to take the drug for one person to benefit. So is it worth taking? That depends. The NNT isn’t crazy high, so you might go for it, especially since a heart attack can kill you. But if the drug has terrible side effects, you might not.

Helminths

Thank FSM the elections are over! Any guesses on who will head the HRD ministry? And the S&T ministry?

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In an on-going effort to keep this blog going, let me start with a link.

An informative Q&A on the state of science behind helminthic therapy, or "the deliberate infection with helminths, or parasitic worms, by swallowing them or letting them crawl through the skin."

Caution: the article is infested with gross pics of worms.

Parachutes, an unproven technology

The British Medical Journal has a fun paper -- Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials -- raising questions about the use of parachutes because its effectiveness has never been proved using a randomized control trial [Hat tip: Fabio Rojas]. This footnote says it all:

Contributors: GCSS had the original idea. JPP tried to talk him out of it. JPP did the first literature search but GCSS lost it. GCSS drafted the manuscript but JPP deleted all the best jokes. GCSS is the guarantor, and JPP says it serves him right.

Links

1. Blog Discovery of the Year: Data Stories (Tag line: "... On India one chart at a time"). It's a personal blog maintained by "a Delhi based journalist" -- that's all we know about the blogger behind this wonderful site. Here's the first post. Here's a post with a catchy title -- We are the 5 %:

   I leave you to draw your own conclusions about what it means to be ‘privileged’ in this country. I also leave you with this question: If the census takers had asked each one of these households, what ‘class’ of society they thought they belonged to, or where they fit in within the income distribution, what do you think their response would have been ( and by ‘their’, I also mean ‘our’)?

2. NYTimes obituary: Robert G. Edwards Dies at 87; Changed Rules of Conception With First ‘Test Tube Baby’.

3. Amy Freitag at Southern Fried Science: I’m a scientist. A social scientist. Please opine on the validity of my discipline.

4. Jenny Rohn at Occam's Corner: Show me the money: is grant writing taking over science?

Links

1. Tarun Jain (Indian School of Business) at Ideas for India: Should Bribe Givers Be Let Off?

   In 2011, Economist Kaushik Basu argued that for a class of bribes, the law should not punish the bribe-giver. This column presents results of experiments conducted to test this idea and provides insights for anti-corruption efforts.

2. Dirk Matten in Globe and Mail: India’s generics drug ruling will help, not hinder, innovation. He reiterates what I consider to be central to the Supreme Court verdict; Indian news outlets that I have seen seem to miss this point, though:

   The crucial point here is whether the version of Glivec for which Novartis was claiming patent protection is actually a ‘ new ‘ drug. What the Indian supreme court in fact ruled was not that Novartis should not enjoy patent protection on their new drugs; it mainly concluded that the new edition of Glivec, for which the company applied for protection, was in fact not sufficiently ‘new’ – not different enough from the old version of Glivec, for which the patent had expired.

   This points to a well know strategy of the pharmaceutical industry. Rather than fighting generic companies, ‘originator’ companies such as Novartis just marginally change the chemical formula of an existing drug whose patent is about to expire and then pretend to having come up with an entirely new one, for which of course they should enjoy full patent protection.

3. Brad Plumer at the Wonk Blog: Expensive batteries are holding back electric cars. Can that change? A part of the argument hinges on the lack of a Morre's Law in energy storage technology!

WaPo Special Report: Biased Research, Big Profits

Peter Whoriskey's story -- As drug industry’s influence over research grows, so does the potential for bias -- starts with research on Avandia (in comparison with two other drugs) in which pretty much everyone had a financial connection with GSK:

Whether these ties altered the report on Avandia may be impossible for readers to know. But while sorting through the data from more than 4,000 patients, the investigators missed hints of a danger that, when fully realized four years later, would lead to Avandia’s virtual disappearance from the United States:

The drug raised the risk of heart attacks.

“If you looked closely at the data that was out there, you could see warning signs,” said Steven E. Nissen, a Cleveland Clinic cardiologist who issued one of the earliest warnings about the drug. “But they were overlooked.”

Doctors, Money, Big Pharma

One more data point:

... ... [T]he Johnson & Johnson episode is also illuminating a broader medical issue: while experts say that doctors have an ethical obligation to warn their peers about bad drugs or medical devices, they often do not do so.

[...] There is another reason doctors may choose to remain silent, experts say: their financial ties to a drug or device maker.

For years, such consulting payments have raised concerns about the impact of money on a doctor’s decision about which drugs to prescribe or how to interpret research findings. Money can also shift a physician’s sense of loyalty, said George Loewenstein, a professor at Carnegie Mellon University who has studied medical conflict-of-interest policies. “If someone has been paying you or employing you, it is very difficult to blow the whistle,” said Professor Loewenstein, who teaches economics and psychology. “It offends our sense of loyalty.”

Vision of Dr. V

Tina Rosenberg has a longish post in NYTimes' Opinionator blog about the late Dr. Govindappa Venkataswamy's brainchild, the Aravind Eye Care System -- a network of eye hospitals and small storefront 'vision centers' in many parts of Tamil Nadu and Kerala:

At Aravind’s hospitals, free patients lodge on a mat on the floor in a 30-person dormitory. Paying patients can choose various levels of luxury, including private, air-conditioned rooms. All patients get best-practice cataract surgeries, but paying patients can choose more sophisticated surgeries with faster recoveries (but not higher success rates). The doctors are identical, rotating between the free and paid wings. [...]

Doctors are hard to find and expensive, so the surgical system is set up to get the most out of them. Patients are prepared before surgery and bandaged afterwards by Aravind-trained nurses. The operating room has two tables. The doctor performs a surgery — perhaps 5 minutes — on Table 1, sterilizes her hands and turns to Table 2. Meanwhile, a new patient is prepped on Table 1. Aravind doctors do more than 2,000 surgeries a year; the average at other Indian hospitals is around 300. As for quality, Aravind’s rate of surgical complications is half that of eye hospitals in Britain.

This volume is key to Aravind’s ability to offer free care. The building and staff costs are the same no matter how many surgeries each doctor performs. High volume means that these fixed costs are spread among vastly more people.

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A previous post (written the day after the great man passed away in 2006) has many more links about Dr. V.

Atul Gawande: 200 Years of Surgery

In the New England Journal of Medicine: Two Hundred Years of Surgery. A breezy -- but pain-filled! -- survey of the developments in surgical methods.

Before anesthesia, the sounds of patients thrashing and screaming filled operating rooms. So, from the first use of surgical anesthesia, observers were struck by the stillness and silence. In London, Liston called ether anesthesia a “Yankee dodge” — having seen fads such as hypnotism come and go — but he tried it nonetheless, performing the first amputation with the use of anesthesia, in a 36-year-old butler with a septic knee, 2 months after the publication of Bigelow's report.10 As the historian Richard Hollingham recounts, from the case records, a rubber tube was connected to a flask of ether gas, and the patient was told to breathe through it for 2 or 3 minutes.12 He became motionless and quiet. Throughout the procedure, he did not make a sound or even grimace. “When are you going to begin?” asked the patient a few moments later. He had felt nothing. “This Yankee dodge beats mesmerism hollow,” Liston exclaimed.

It would take a little while for surgeons to discover that the use of anesthesia allowed them time to be meticulous. Despite the advantages of anesthesia, Liston, like many other surgeons, proceeded in his usual lightning-quick and bloody way. Spectators in the operating-theater gallery would still get out their pocket watches to time him. The butler's operation, for instance, took an astonishing 25 seconds from incision to wound closure. (Liston operated so fast that he once accidentally amputated an assistant's fingers along with a patient's leg, according to Hollingham. The patient and the assistant both died of sepsis, and a spectator reportedly died of shock, resulting in the only known procedure with a 300% mortality.)

Indian Higher Ed Links

These news items seem significant, but I haven't seen a focused discussion of what led to these decisions and what they might mean on the ground. Let me park them here for the moment:

1. Aarthi Dhar in The Hindu: Doctors pursuing higher studies in the US to sign return bond.

2. Linah Baliga in ToI: Govt bans use of live animals for education, research.

Research on Asterix et al

Following a comment by L that "As for actual comic books, Asterix deserves a thesis," I did a quick Google Scholar search for Asterix Obelix, and was surprised to find some 2400+ entries.

Long story short: most of it is pretty grim [see footnote], but this one is a gem: Traumatic brain injuries in illustrated literature: experience from a series of over 700 head injuries in the Asterix comic books. You can imagine the researchers having a lot of fun, and laughing all the way to their academic CV with a "Clinical Article". To paraphrase Asterix, "These Germans are crazy!"

Here's the abstract:

Background The goal of the present study was to analyze the epidemiology and specific risk factors of traumatic brain injury (TBI) in the Asterix illustrated comic books. Among the illustrated literature, TBI is a predominating injury pattern.

Methods A retrospective analysis of TBI in all 34 Asterix comic books was performed by examining the initial neurological status and signs of TBI. Clinical data were correlated to information regarding the trauma mechanism, the sociocultural background of victims and offenders, and the circumstances of the traumata, to identify specific risk factors.

Results Seven hundred and four TBIs were identified. The majority of persons involved were adult and male. The major cause of trauma was assault (98.8%). Traumata were classified to be severe in over 50% (GCS 3–8). Different neurological deficits and signs of basal skull fractures were identified. Although over half of head-injury victims had a severe initial impairment of consciousness, no case of death or permanent neurological deficit was found. The largest group of head-injured characters was constituted by Romans (63.9%), while Gauls caused nearly 90% of the TBIs. A helmet had been worn by 70.5% of victims but had been lost in the vast majority of cases (87.7%). In 83% of cases, TBIs were caused under the influence of a doping agent called “the magic potion”.

Conclusions Although over half of patients had an initially severe impairment of consciousness after TBI, no permanent deficit could be found. Roman nationality, hypoglossal paresis, lost helmet, and ingestion of the magic potion were significantly correlated with severe initial impairment of consciousness (p≤0.05).

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Footnote: A lot of the hits are from some particle physics experiments by groups named ASTERIX collaboration and OBELIX collaboration. Which is kinda fun in a geeky-quarky sort of way, but they ended up polluting the search results on research on Asterix.

Links ...

1. Kathryn Hume: Giving a Job Talk. Buried in some seriously great advice is this little nugget about the role of "class" in faculty recruitment:

   How you pitch your argument will depend on the institution interviewing you. A few very elite universities believe in intellectual hazing, and will think you a wimp if you don’t try to cow them with a brilliant, jargon-laden analysis. If you come from such a department, you presumably know how this game is played and can prepare for it, and only people from that kind of university are likely to be invited for a campus visit. Most departments are more welcoming and friendly; they want a good colleague with whom exchanging ideas will be fun, not someone determined to bully them intellectually in every exchange. You may meet someone who emerged from that kind of training in the audience, and that person may try to give you a hard time in the Q and A, but most of your potential colleagues don’t feel the need to prove themselves that way.[Bold emphasis added]

2. Matt McAllester: America is Stealing Foreign Doctors:

   As we sat in the cafeteria, I suggested [to Indian-Zambian doctor Kunj Desai] that if he did return to Zambia, he might be seen as something of a returning hero. Desai is a naturally polite and courteous man, but he is also disinclined to hold back from criticizing when he finds fault. In this case, his target was himself. He looked at the table and said: “The heroes are the guys that stayed. They didn’t quit, and they didn’t run away.”

Dr. Ken Murray on How Doctors Die

The subtitle -- It’s Not Like the Rest of Us, But It Should Be -- is a little cryptic, but these early paragraphs present a good summary of how doctors choose to live their last days, weeks and months:

It’s not a frequent topic of discussion, but doctors die, too. And they don’t die like the rest of us. What’s unusual about them is not how much treatment they get compared to most Americans, but how little. For all the time they spend fending off the deaths of others, they tend to be fairly serene when faced with death themselves. They know exactly what is going to happen, they know the choices, and they generally have access to any sort of medical care they could want. But they go gently.

Of course, doctors don’t want to die; they want to live. But they know enough about modern medicine to know its limits. And they know enough about death to know what all people fear most: dying in pain, and dying alone. They’ve talked about this with their families. They want to be sure, when the time comes, that no heroic measures will happen—that they will never experience, during their last moments on earth, someone breaking their ribs in an attempt to resuscitate them with CPR (that’s what happens if CPR is done right).

See also: Paula Span's post at The New Old Age blog at NYTimes:

Dr. Murray contends in his post that doctors know too much about the futility of aggressive end-of-life treatment to subject themselves to it. His argument is anecdotal, based on people he has known but lacking statistical underpinnings. “It’s a fair criticism,” he said.

But recently an alert reader e-mailed him a study, published in 2008 in The Archives of Internal Medicine, of more than 800 physicians who graduated from Johns Hopkins University between 1948 and 1964. Most had reached their late 60s and 70s, so questions about end-of-life treatment were not purely hypothetical.

Asked what treatment they would accept if they’d suffered irreversible brain damage that left them unable to speak or recognize people but was not terminal, the doctors overwhelmingly said they’d decline CPR, feeding tubes and a host of other common interventions. “So there is actual evidence about this,” Dr. Murray said, pleased.

Drug Reps' Tactics

After posting Dr. E.A.S. Sarma's warning about the potential for conflict of interest created by research funding by industry, let me follow it up with a link to Dan Ariely's description of drug reps' tactics in getting doctors to compromise on their ethics:

... One clever tactic that they used was to hire physicians to give a brief lecture to other physicians about a drug. Now, they really didn’t care what the audience took from the lecture, but were actually interested in what the act of giving the lecture did to the speaker himself. They found that after giving a short lecture about the benefits of a drug, the speaker would begin to believe his own words and soon prescribe accordingly. Psychological studies show that people quickly start believing what is coming out of their own mouths, even when they are paid to say it. This is a clear case of cognitive dissonance at play; doctors reason that if they are touting this drug, they must believe in it themselves — and so they change their beliefs to match up with their speech.

The reps employed other tricks like switching on and off various accents, personalities, political affiliations, and basically served as persuasion machines (they may have mentioned the word “chameleon”). They were great at putting doctors at ease, relating to them as similar working people who go deep-sea fishing or play baseball together as peers. They used these shared experiences to develop an understanding that the physicians write prescriptions for their “friends.” The physicians, of course, did not think that they were compromising their values when they were out playing with the drug reps.

That last sentence sums it up nicely: the trick is to play this game in which doctors become "willing victims." There's quite a bit of literature on such shady tactics (some of which could be quite unsubtle): see, for example, articles by Marcia Angell and Daniel Carlat. There have also been several news stories.

Peter Kramer: "In Defence of Antidepressants"

Critics raise various concerns, but in my view the serious dispute about antidepressant efficacy has a limited focus. Do they work for the core symptoms (such as despair, low energy and feelings of worthlessness) of isolated episodes of mild or moderate depression? The claim that antidepressants do nothing for this common condition — that they are merely placebos with side effects — is based on studies that have probably received more ink than they deserve.

More here. A rebuttal of sorts to the NYRB articles by ex-JAMA editor Marcia Angell [See this post for links. Thanks to commenter Vijay for the pointer ]