Medicine

This book already has done a good deal to raise the status of autistic people and also studies of autism.  Silberman is to be commended for extensive research into the lives of Hans Asperger and Leo Kanner and into the modern “neurodiversity” movement more broadly.  He has taken on a very difficult topic and turned it into what is likely to prove a commercially successful book.

That said, most reviews of this work, while positive, are not very assured.  It’s as if the reviewers know they are not well-informed about the topic and thus they stick to general praise, without delving into the details.  Or maybe they like the book’s conclusion and are reluctant to criticize the work as a whole.  I, in contrast, have a few more pointed remarks:

1. Leo Kanner, a co-discoverer of autism, is made out to be the bad guy, yet his writings are more subtle than Silberman indicates, even though one can pull some bad phrases and quotations.  Kanner in particular had a much stronger grasp of the diversity within autism (pdf) than Silberman grants.  It is hard, after reading that piece, to see how his conception of autism could be described as monolithic.

The contrast between Kanner and Asperger is much overdrawn.  The truth is closer to “they both had profound early insights and were unjustly neglected” rather than Silberman’s “sadly the Kanner approach to autism at first beat out the Asperger approach.”  The latter narrative is an over-dramatized storytelling convention of a popular book.  The real problem back then was how various minorities and “deviants” were treated, from gay individuals to lobotomized schizophrenics, rather than the dominant influence of Kanner’s ideas.

2. Silberman promotes an “along a spectrum (spectra?) model” rather than an “autistic yes or no” model.  Maybe so, but it is far from obvious that the “yes or no” model is false and in fact it explains some of the data better (pdf).  Silberman offers no scientific reason for his choice, and he doesn’t define the underlying concepts clearly enough to outline exactly what is at stake.  Silberman argues that the spectrum models are ethically superior and more humane, but that is an unjustified presumption and it also does not settle the substantive dispute.  In any case both models are capable of accommodating either respectful or disrespectful attitudes toward autistic people.

3. For a 534-pp.book on autism, there is oddly little discussion of what autism is or might be.  That is author’s prerogative of course, but it means the book doesn’t offer much of a framework for judging the research history of autism, as it attempts to do.

4. Silberman devotes an entire chapter to the movie “Rain Man,” and in part the movie’s main role model, namely Kim Peek.  Yet the text fails to note it eventually turned out that Peek was not in fact autistic but instead probably had FG syndrome.  This is another instance of the book’s tendency to prefer a good story over the facts.  And that Peek was so ingloriously railroaded into the autism category is part of the actual story there (Dustin Hoffman played a role in doing that), yet that is a mistake which Silberman himself essentially repeats.

I hate to rain on the parade of this book because a) I love the topic, b) the author’s research is impressive, and c) the book is genuinely humane and tolerant and it will have an almost entirely positive impact on popular discourse.  Still, I think that the original organizing themes in the work are mostly wrong.

And oddly, for all its praise of autism and autistic ways of thinking, the style of the book is remarkably non-autistic.  It’s full of long stories and blah blah blah, rather than getting to the point.

Here is a review from Nature.  Carl Zimmer interviews Silberman.  Here is The Economist review.  Here is a related podcast.  Here is the Jennifer Senior NYT review.  Here is Silberman’s LATimes piece.  Here is a Morton Ann Gernsbacher review.  Here is The Guardian.  Here is The Atlantic.  Here is a PLOS interview with Silberman.

It’s an interesting read, but I don’t think you can trust what’s in there.

I have long argued that the FDA has an incentive to delay the introduction of new drugs because approving a bad drug (Type I error) has more severe consequences for the FDA than does failing to approve a good drug (Type II error). In the former case at least some victims are identifiable and the New York Times writes stories about them and how they died because the FDA failed. In the latter case, when the FDA fails to approve a good drug, people die but the bodies are buried in an invisible graveyard.

In an excellent new paper (SSRN also here) Vahid Montazerhodjat and Andrew Lo use a Bayesian analysis to model the optimal tradeoff in clinical trials between sample size, Type I and Type II error. Failing to approve a good drug is more costly, for example, the more severe the disease. Thus, for a very serious disease, we might be willing to accept a greater Type I error in return for a lower Type II error. The number of people with the disease also matters. Holding severity constant, for example, the more people with the disease the more you want to increase sample size to reduce Type I error. All of these variables interact.

In an innovation the authors use the U.S. Burden of Disease Study to find the number of deaths and the disability severity caused by each major disease. Using this data they estimate the costs of failing to approve a good drug. Similarly, using data on the costs of adverse medical treatment they estimate the cost of approving a bad drug.

Putting all this together the authors find that the FDA is often dramatically too conservative:

…we show that the current standards of drug-approval are weighted more on avoiding a Type I error (approving ineffective therapies) rather than a Type II error (rejecting effective therapies). For example, the standard Type I error of 2.5% is too conservative for clinical trials of therapies for pancreatic cancer—a disease with a 5-year survival rate of 1% for stage IV patients (American Cancer Society estimate, last updated 3 February 2013). The BDA-optimal size for these clinical trials is 27.9%, reflecting the fact that, for these desperate patients, the cost of trying an ineffective drug is considerably less than the cost of not trying an effective one.

(The authors also find that the FDA is occasionally a little too aggressive but these errors are much smaller, for example, the authors find that for prostate cancer therapies the optimal significance level is 1.2% compared to a standard rule of 2.5%.)

The result is important especially because in a number of respects, Montazerhodjat and Lo underestimate the costs of FDA conservatism. Most importantly, the authors are optimizing at the clinical trial stage assuming that the supply of drugs available to be tested is fixed. Larger trials, however, are more expensive and the greater the expense of FDA trials the fewer new drugs will be developed. Thus, a conservative FDA reduces the flow of new drugs to be tested. In a sense, failing to approve a good drug has two costs, the opportunity cost of lives that could have been saved and the cost of reducing the incentive to invest in R&D. In contrast, approving a bad drug while still an error at least has the advantage of helping to incentivize R&D (similarly, a subsidy to R&D incentivizes R&D in a sense mostly by covering the costs of failed ventures).

The Montazerhodjat and Lo framework is also static, there is one test and then the story ends. In reality, drug approval has an interesting asymmetric dynamic. When a drug is approved for sale, testing doesn’t stop but moves into another stage, a combination of observational testing and sometimes more RCTs–this, after all, is how adverse events are discovered. Thus, Type I errors are corrected. On the other hand, for a drug that isn’t approved the story does end. With rare exceptions, Type II errors are never corrected. The Montazerhodjat and Lo framework could be interpreted as the reduced form of this dynamic process but it’s better to think about the dynamism explicitly because it suggests that approval can come in a range–for example, approval with a black label warning, approval with evidence grading and so forth. As these procedures tend to reduce the costs of Type I error they tend to increase the costs of FDA conservatism.

Montazerhodjat and Lo also don’t examine the implications of heterogeneity of preferences or of disease morbidity and mortality. Some people, for example, are severely disabled by diseases that on average aren’t very severe–the optimal tradeoff for these patients will be different than for the average patient. One size doesn’t fit all. In the standard framework it’s tough luck for these patients. But if the non-FDA reviewing apparatus (patients/physicians/hospitals/HMOs/USP/Consumer Reports and so forth) works relatively well, and this is debatable but my work on off-label prescribing suggests that it does, this weighs heavily in favor of relatively large samples but low thresholds for approval. What the FDA is really providing is information and we don’t need product bans to convey information. Thus, heterogeneity plus a reasonable effective post-testing choice process, mediates in favor of a Consumer Reports model for the FDA.

The bottom line, however, is that even without taking into account these further points, Montazerhodjat and Lo find that the FDA is far too conservative especially for severe diseases. FDA regulations may appear to be creating safe and effective drugs but they are also creating a deadly caution.

Hat tip: David Balan.

The Nature article is here.  The FT put it differently: “Scientists make breakthrough in search for universal flu vaccine”  Here are many other articles on the same.

And how long did it take us, starting more or less from scratch, to make that Ebola vaccine?

Is it possible that our vaccine development capacity is seriously better than say ten years ago?

Are the biggest potential winners China, India, Indonesia, and Nigeria?

For a relevant pointer I thank J.

Can you guess my answer to that question?  But it does seem to be coming:

After decades of unregulated existence in all 50 states, the booming field of personal trainers is braced for a wave of scrutiny that is expected to transform the industry and could make or break some of the biggest fitness companies in the country.

The new regulations, being written by and for the nation’s capital city, will create a registry of all personal trainers in the District only. But they are expected to become a model that winners and losers in the fight believe will be replicated elsewhere.

The credit or blame, as you may care to describe it, goes to the Affordable Care Act:

A variety of workplace wellness programs and preventive health-care initiatives called for in the law could soon translate into rivers of billable hours for those with credentials to keep American waistlines in check.

And that means the race is on to be eligible for those credentials…

I believe the excess bureaucratization of the ACA is just beginning to show all of its implications…

The story is by Aaron C. Davis.  And the article is sad throughout:

“We all have heard anecdotal reports of injuries, sexual misconduct and misrepresentation of titles by persons claiming to be competent in that area,” Simpson testified before a D.C. Council committee. She called the lack of any registration or licensure of personal trainers “a nationwide failure.”

Well, that is one “failure” we seem to be on the verge of remedying…

cryo

While Anastasia Garvey, an actress and model, doesn’t have office pressure, she says she is constantly on edge wondering if she’ll get a certain job. She has developed a regimen of ways to disconnect: meditation, acupuncture, cupping therapy, monthly trips to a reservation-only spa and most recently cryotherapy — as in spending some time being blasted by air cooled to minus 260 degrees.

It only lasts three minutes, plus time to warm up again on a stationary bike, but it costs $90 a session, she said. She goes three times a week.

“The first time I did it I couldn’t remember my name,” she said. “You’re in a freezer. You’re so cold you can’t think of anything.”

There are many interesting ideas and bits in this NYT Paul Sullivan piece: “As for the seeming contradiction of the Buddhist boxer…”

From the comments — on suicide

by on August 22, 2015 at 2:09 am in Law, Medicine, Philosophy | Permalink

Switzerland tolerates assisted suicide since 1942 and there are very interesting numbers. A) From 1995 to 2009, assisted suicide cases have grown but the total number of suicides keeps constant. B) Assisted suicide in 2009 accounted for approx 30% of all suicides. C) Women chose assisted suicide more than men, but men use firearms more than women to commit suicide. D) Peak assisted suicide is between 75 and 84 years old. It seems that people that cross the 80+ years old line are not affected by painful or exhausting diseases thus they choose to life until it ends naturally E) Peak suicide is between 45-54 years old, midlife crisis is real, F) Overall suicide rates for women kept constant even if assisted suicide rates increase. G) Overall suicide rates for men are going down and assisted suicide goes up.

http://www.bfs.admin.ch/bfs/portal/en/index/news/publikationen.html?publicationID=4732

The overall suicide rate in Netherlands between 1999 and 2013 has been between 8.3 and 11 per 100K habitats. The lowest rate was just before the crisis. http://www.cbs.nl/nl-NL/menu/themas/gezondheid-welzijn/publicaties/artikelen/archief/2015/4320-suicide-in-noord-holland-noord-en-nederland1999-2013.htm

The WaPo article would lose its killer headline if the total suicide rate is considered when assessing the “exponential” increase of assisted suicide. This seems like another case of double standards. When someone blows their brains with a gun we have to respect the decision and comfort the family, when someone opens the valve of sodium thiopental with their hand…..it’s just wrong.

That is from Axa.

In 2013, euthanasia accounted for one of every 28 deaths in the Netherlands, three times the rate of 2002. In the Dutch-speaking part of Belgium, one of every 22 deaths was due to euthanasia in 2013, a 142 percent increase since 2007. Belgium has legalized euthanasia for children under 12, though only for terminal physical illness; no child has yet been put to death.

That is from Charles Lane.

Bowen and Casadevall have a new PNAS paper on this question:

The general public funds the vast majority of biomedical research and is also the major intended beneficiary of biomedical breakthroughs. We show that increasing research investments, resulting in an increasing knowledge base, have not yielded comparative gains in certain health outcomes over the last five decades. We demonstrate that monitoring scientific inputs, outputs, and outcomes can be used to estimate the productivity of the biomedical research enterprise and may be useful in assessing future reforms and policy changes. A wide variety of negative pressures on the scientific enterprise may be contributing to a relative slowing of biomedical therapeutic innovation. Slowed biomedical research outcomes have the potential to undermine confidence in science, with widespread implications for research funding and public health.

Carolyn Johnson summarizes the results of the paper:

Casadevall and graduate student Anthony Bowen used a pretty straightforward technique to try and answer the question. They compared the NIH budget, adjusted for inflation, with the number of new drugs approved by the Food and Drug Administration and the increases in life expectancy in the U.S. population over the same time period.

Those crude health measures didn’t keep pace with the research investment. Funding increased four-fold since 1965, but the number of drugs only doubled. Life expectancy increased steadily, by two months per year.

Johnson also covers some useful responses from the critics.  The result also may say more about the NIH than about progress per se.  And here is a more optimistic take from Allison Schraeger.

Observers seem to focus on the target event and not its complement.  Bagchi and Ince have a new paper on this question:

Consumers routinely rely on forecasters to make predictions about uncertain events (e.g., sporting contests, stock fluctuations). The authors demonstrate that when forecasts are higher versus lower (e.g., a 70% vs. 30% chance of team A winning a game) consumers infer that the forecaster is more confident in her prediction, has conducted more in-depth analyses, and is more trustworthy. The prediction is also judged as more accurate. This occurs because forecasts are evaluated based on how well they predict the target event occurring (team A winning). Higher forecasts indicate greater likelihood of the target event occurring, and signal a confident analyst, while lower forecasts indicate lower likelihood and lower confidence in the target event occurring. But because, with lower forecasts, consumers still focus on the target event (and not its complement), lower confidence in the target event occurring is erroneously interpreted as the forecaster being less confident in her overall prediction (instead of more confident in the complementary event occurring—team A losing). The authors identify boundary conditions, generalize to other prediction formats, and demonstrate consequences.

Of course this also has relevance for the evolutionary processes governing pundits.

Here is a related press release (pdf).  For the pointer I thank Charles Klingman.

FDA approval at what price?

by on August 13, 2015 at 11:33 am in Economics, Law, Medicine, Science | Permalink

There is plenty of debate over whether the FDA should be looser or tougher with new drug approval, but I rarely hear the question posed as “approval at what price?”

One option would be to approve relatively strong and safe drugs at full Medicare and Medicaid reimbursement rates, if not higher.  Drugs with lesser efficacy or higher risk could be approved at lower reimbursement prices.  It is possible or perhaps even likely, of course, that private insurance companies would follow the government’s lead.

Dr. Peter Bach has promoted one version of this idea, and produced a calculator for valuing these drugs.  In essence the government would be saying to lower quality producers “yes, you can continue to try to improve this drug, but not at public expense.”

I believe proposals of this kind deserve further attention, and in general the notion of regulatory approval need not be conceived in strictly binary, yes/no terms.

Sentences to ponder

by on August 12, 2015 at 1:24 pm in Education, Medicine, Philosophy, Science | Permalink

We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence.

That is from “a whole bunch of guys” writing in Molecular Psychiatry, via Michelle Dawson.  In other words, the prospect of straightforward genetic engineering for smarter babies probably won’t be a reality anytime soon.  Technology remains pretty far behind the matchmaker.

WSJ: A federal court in New York delivered a setback to the Food and Drug Administration, ruling the agency can’t bar a drug company from marketing a pill for off-label use as long as the claims are truthful.

The decision by the federal district court in the Southern District of New York, is the latest of a line of such cases. It concerns the Irish company Amarin Pharma Inc. and its fish-oil-derived drug Vascepa, and it has been closely watched by the pharmaceutical industry. The company asked the court to stop the FDA from enforcing its off-label marketing ban, and the court agreed.

The ruling is important because in the last few years the FDA has extracted billions of dollars in settlements from pharmaceutical firms for engaging in what appears to be constitutionally protected speech. In fact, the courts have repeatedly ruled that FDA and Congressional restrictions on truthful and non-misleading off-label marketing are unconstitutional.

In Washington Legal Foundation v. Friedman, for example, the DC court issued an injunction preventing the FDA from prohibiting, restricting, sanctioning or otherwise seeking to limit pharmaceutical and device manufactures from disseminating information about off-label uses from peer-reviewed professional journals or textbooks. In U.S. v. Caronia the court (2nd circuit) reversed a criminal conviction and said that the FDA cannot criminalize truthful promotion of off-label uses of approved drugs. Indeed, the court in that case defended the utility of such promotion:

…prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use “paternalistically” interferes with the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions. See Va. Bd. of Pharmacy v. Va. Citizens Consumer Council, Inc., 425 U.S. 748, 770 (1976)

…See also Sorrell, 131 S. Ct. at 2670- 72 (“[The] fear that [physicians, sophisticated and experienced customers,] would make bad decisions if given truthful information” cannot justify content-based burdens on speech.”) (citing sources);

…Liquormart, 517 U.S. at 503 (“[B]ans against truthful, nonmisleading commercial speech . . . usually rest solely on the offensive assumption that the public will respond ‘irrationally’ to the truth. . . . The First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good.”).

In Washington Legal Foundation v. Henney the court summed up concisely:

The First Amendment is premised upon the idea that people do not need the government’s permission to engage in truthful, nonmisleading speech about lawful activity.

(By the way, it’s this line of cases that makes me think that 23andMe has a strong first amendment case for presenting to customers information about their own DNA.)

The courts were exactly correct. Off-label uses of approved drugs are a vital part of the discovery process of modern medicine. New uses for old drugs are often discovered through serendipity and close observation in the field. Indeed, modern medicine moves faster than the FDA and it often happens that the first-line therapy is an off-label treatment. Prohibiting firms from truthfully discussing such treatments with physicians is not just unconstitutional it’s also paternalistic and harmful to patient welfare.

This case, Amarin v FDA, is especially egregious because the company wants to discuss with physicians the results of its own FDA-approved trial. Amarin has a fish-oil derived drug designed to reduce triglyceride levels and it already has approval to sell and market this drug in patients with very high levels of triglycerides. It also wanted approval to sell the drugs in patients with high (but not very high levels) and it conducted an FDA-approved trial that showed that the drug is safe and effective at reducing triglyceride levels in this set of patients.

Although the trial was successful the FDA, for reasons discussed below, refused to grant approval. Amarin isn’t disputing the refusal but they wanted to tell physicians the results of the trial and then let the physicians and their patients decide whether reducing triglyceride levels is something that they want to do given currently existing evidence about triglyceride levels and heart attacks. The FDA threatened to pursue civil and possibly criminal charges but the court has now precluded the FDA from those pursuits.

Aside from the first amendment issues, the case is also interesting as another example of how a capricious FDA can kill innovation through regulation uncertainty. (The story is similar in many respects to that told by Joseph Gulfo in Innovation Breakdown, see my review).

To wit: Amarin wanted approval to sell its drug to patients with high levels of triglycerides and they obtained a special protocol agreement (SPA) from the FDA to run a study in this population. Quoting the court:

An SPA agreement is a written agreement that a manufacturer may enter into with the FDA, which sets out the design and size parameters for clinical trials of a new drug, and the conditions under which the FDA would approve the drug. For the manufacturer, such an agreement minimizes development risk by providing regulatory predictability: Provided that the manufacturer follows the procedure set in the SPA agreement and the drug proves meets the benchmarks for effectiveness set in the agreement, the FDA must approve the drug.

The results of the study were good:

The ANCHOR study achieved each numeric objective that the SPA Agreement had set: The results showed that Vascepa produced a statistically significant decrease in triglyceride levels in persons with persistently high triglycerides, as well as in other lipid, lipoprotein, and inflammatory biomarkers.

…Because Amarin had met all requirements for approval set out in the ANCHOR SPA Agreement, Amarin anticipated that the FDA would approve Vascepa for the additional use that Amarin sought, i.e., by patients with persistently high triglycerides.

Instead of approving the drug, however, the FDA rescinded their agreement. The FDA argued that although the drug did reduce triglyceride levels it was no longer certain that reducing triglyceride levels would reduce cardiovascular events.

Can you imagine the tailspin this sent researchers at Amarin into when they learned that the drug would not be approved despite passing all the agreed upon tests? (Read Gulfo for a vivid account of his case).

Who will invest in bio-medical advances with this kind of risk? Sergei Brin said that he didn’t want to invest in health care because “It’s just a painful business to be in . . . the regulatory burden in the U.S. is so high that I think it would dissuade a lot of entrepreneurs.” It’s precisely this kind of regulatory uncertainty that an SPA was meant to avoid. By rescinding their agreement, the FDA is sending the message to investors that no one is safe.

There is a newly published paper by Andrew Beauchamp:

The U.S. abortion market has grown increasingly concentrated recently, while many states tightened abortion laws. Using data on abortion providers, I estimate an equilibrium model of demand, price competition, entry and exit, to capture the effect of regulation on industry dynamics. Estimates show regulations played an important role in determining the abortion market structure and evolution. Counterfactual simulations reveal increases in demand-aimed regulation were the most important observed factor in explaining recent abortion declines. Simulating Utah’s regulatory regime nationally shows tightening abortion restrictions can increase abortions in equilibrium, mainly through tilting the competitive landscape toward low-price providers.

There are ungated versions here, and for the pointer I thank the excellent K.

The authors are Nobel Laureates George A. Akerlof and Robert J. Shiller and the subtitle is The Economics of Manipulation and Deception.  It’s a popular take on how markets trap you and your preferences in places you don’t want to be.  Self-recommending of course.

There are chapters on advertising, tobacco, alcohol, junk bonds, credit cards, pharmaceuticals (some), and yes government.  My main complaint about the book is that its chooses easy targets and doesn’t puncture enough sacred cows.  For instance the chapter on government criticizes spending money on lobbying, whereas I would have preferred an attempt to show that an apparently beneficial and popular institution is in fact bad and appealing to the weaker elements in our preferences.  I wonder to what extent what the authors call “The Resistance and its Heroes” is in fact another example of…phishing for phools.  In other words, I wish this book were more Hansonian.

By the way, I have never eaten too much ice cream.

That was my response to reading Ta-Nehisi Coates’s Between the World and Me.  We all overinvest in non-diversified mood affiliation portfolios, so why not read someone else’s non-diversified mood affiliation portfolio from a less common point of view?

The writing I thought was superb and also original, so I agree with the take of Christopher Hayes on Twitter:

Read book because the writing itself is in many ways more important and essential than the *argument* it’s making.

Many of you will object to this book, and not entirely for incorrect reasons.  This is a fire hose but there is not much if any engagement with potentially contradictory facts.  And if you read only this book, and otherwise would know nothing of America, you would not come close to guessing national black per capita income.

Still, if you’re wondering whether or not you should pick it up, I will nudge you in the direction of “yes.”

Here is a good article on the author.