Category: Medicine

Why are so many graduate students depressed?

PhD and master’s students worldwide report rates of depression and anxiety that are six times higher than those in the general public (T. M. Evans et al. Nature Biotech. 36, 282–284; 2018). The report, based on the responses of 2,279 students in 26 nations, found that more than 40% of respondents had anxiety scores in the moderate to severe range, and that nearly 40% showed signs of moderate to severe depression.

That is from this summary statement.  Here is the original piece.  So what might be going on here?

1. The ordeal of studying and possibly finishing is extreme, and extreme ordeals depress people.  This seems inconsistent with other evidence, however, namely rising (reported) rates of depression in prosperous, comfortable societies.

2. The task of studying and possibly finishing is correlated with a kind of extreme lassitude, and that in turn is correlated with depression.

3. Graduate students become depressed as they realize they have chosen poor life paths.

4. Graduate students become depressed as they realize, a’la Caplan, that it is mostly about signaling.

5. Graduate students are undergoing a transformation of their personalities, and being turned into intellectual elites, but this process is traumatic in several regards, thus leading to frequent depression.  The chance of depression is part of the price of admission to a select club.

6. Our graduate institutions serve women poorly (women in graduate school experience depression at higher rates — 41% vs 35% for the men).

7. It’s all just sample bias, as depressed graduate students have nothing better to do than respond to this survey.

What else?  And how much should we regard these results are symptoms of a deeper malaise?  Or is the problem confined mainly to academic life?

How FDA-Approved Prescribing Information Lags Behind Real-World Clinical Practice

Once a drug has been approved for some use it can be legally prescribed for any use. New uses for old drugs are often discovered. When physicians learn of these new uses, prescribing practices move beyond the uses that the FDA has evaluated and permitted. In Outdated Prescription Drug Labeling, Shea et al. compare off-label uses for cancer drugs that are graded as “well-accepted” by the National Comprehensive Cancer Drugs & Biologics Compendium (NCCN) with the labelled, “FDA-approved” uses. What they find is that most drugs have multiple off-label uses that are significantly different from FDA approved uses.

Our analysis of the NCCN Compendium and FDA drug labels for 43 cancer drugs approved between 1999 and 2011 identified hundreds of off-label uses, most of which were strongly supported by NCCN expert panels.

…Additionally, of the 253 off-label uses, 165 (65.2%) were categorized as “new indications,” meaning they were in disease settings not represented on labels

In my work on off-label prescribing (and with Klein) I have emphasized that the off-label world offers a window on what the larger world would look like with much less FDA control over new drug approvals. Notice that even today it’s physicians and the private approval process, as represented by the compendia, that determine actual prescribing and payment.

We found that 4 of the 5 largest private payers, as well as Medicare, cover over 90% of uses listed on the NCCN Compendium (uses graded 1 and 2A), suggesting widespread acceptance of these uses by diverse stakeholders. While standards for FDA approval differ from standards for coverage determinations, these findings indicate that the gulf between labeled uses and covered uses may be needlessly wide.

To bring FDA labeling up to real-world practice the authors recommend “a collaboration between the FDA and the developers of clinical guidelines and drug compendia to evaluate existing evidence about approved drugs and suggest updates to labeling.” In other words, the decentralized, private approval system should be used to determine which new uses of old drugs are safe and effective and those determinations should then be adopted by the FDA. I agree. But if private practices can be used to approve new uses for old drugs, why shouldn’t similar procedures be used to approve new uses for new drugs?

Opioids are not mainly an economic phenomenon

Overall, our findings suggest that there is no simple causal relationship between economic conditions and the abuse of opioids. Therefore, while improving economic conditions in depressed areas is desirable for many reasons, it is unlikely to curb the opioid epidemic.

That is from Janet Currie, Jonas Y. Jin, and Molly Schnell in a new NBER working paper.

What should I ask Balaji Srinivasan?

I will be doing a Conversation with him, no associated public event.  Here is his home page, here is his bio:

Balaji S. Srinivasan is the CEO of Earn.com and a Board Partner at Andreessen Horowitz. Prior to taking the CEO role at Earn.com, Dr. Srinivasan was a General Partner at Andreessen Horowitz. Before joining a16z, he was the cofounder and CTO of Founders Fund-backed Counsyl, where he won the Wall Street Journal Innovation Award for Medicine and was named to the MIT TR35.

Dr. Srinivasan holds a BS, MS, and PhD in Electrical Engineering and an MS in Chemical Engineering from Stanford University. He also teaches the occasional class at Stanford, including an online MOOC in 2013 which reached 250,000+ students worldwide.

His latest Medium essay was on ICOs and tokens.  I thank you all in advance for your wise counsel.

Longevity FAQ

From Laura Deming, you will find it here, essential reading for our time.  Here is one bit:

Senescence

at a glance: a fraction of your cells get older than the others, so we’d like to eliminate them

As you get old, so do your cells. But some of your cells get old in a way that is much worse than the others. You may have heard of a thing called telomerase. If you remember correctly, it’s the thing that keeps the end of your DNA long enough that your cells can still divide. When one of your cells runs out of telomerase, it can’t make many more copies of itself. If the cell sticks around, refuses to die even when it stops working, and starts secreting signals to the immune system, we call that a ‘senescent cell‘.

What happens when you get rid of these cells? Some animals that age faster than normal have a lot of these ‘senescent cells’ and are good experimental models in which to ask that question. In 2011, a group from the Mayo Clinic cleared out many of the senescent cells in one of those animal models, and found that the resulting mice were healthier in old age (among other things, they did not get cataracts and bent spines, which typically emerge in old age). In 2016, the same investigators found that getting rid of senescent cells in normal mice made them live a longer healthy lifespan. Knocking out senescent cells is tricky, because they don’t have many unique identifiers. Companies are working to either find things empirically that kill senescent cells, or figure out specific mechanisms by which to try to destroy them.

It starts off like this:

Hi! I’m Laura Deming, and I run Longevity Fund. I spend a lot of time thinking about what could increase healthy human lifespan. This is my overview of the field for beginners.

Does it end with you living to 129?  I genuinely do not know.

My Conversation with Robin Hanson

I am honored to have been able to do this, here is the podcast and transcript.  The topics we covered included…the ideas of Robin, most of all: “With Robin, we go meta. Robin, if politics is not about policy, medicine is not about health, laughter is not about jokes, and food is not about nutrition, what are podcasts not about?”

Here is one exchange:

COWEN: Let’s say I’m an introvert, which by definition is someone who’s not so much out there. Why is that signaling? Isn’t that the opposite of signaling? If you’re enough of an introvert, it doesn’t even seem like countersignaling. There’s no one noticing you’re not there.

HANSON: I’ve sometimes been tempted to classify people as egg people and onion people. Onion people have layer after layer after layer. You peel it back, and there’s still more layers. You don’t really know what’s underneath. Whereas egg people, there’s a shell, and you get through it, and you see what’s on the inside.

In some sense, I think of introverts as going for the egg people strategy. They’re trying to show you, “This is who I am. There’s not much more hidden, and you get past my shell, and you can know me and trust me. And there’s a sense in which we can form a stronger bond because I’m not hiding that much more.”

And:

COWEN: Here’s another response to the notion that everything’s about signaling. You could say, “Well, that’s what people actually enjoy.” If signaling is 90 percent of whatever, surely it’s evolved into being parts of our utility functions. It makes us happy to signal. So signaling isn’t just wasteful resources.

What we really want to do is set up a world that caters to the elephant in our brain, so to speak. We just want all policies to pander to signaling as much as possible. Maybe make signals cheaper, but just signals everywhere now and forever. What says you?

HANSON: I think our audience needs a better summary of this thesis that I’m going to defend here. The Elephant in the Brain main thesis is that in many areas of life, perhaps even most, there’s a thing we say that we’re trying to do, like going to school to learn or going to the doctor to get well, and then what we’re really trying to do is often more typically something else that’s more selfish, and a lot of it is showing off.

If that’s true, then we are built to do that. That’s the thing we want to do, and in some sense it’s a great world when we get to do it.

My complaint isn’t really that most people don’t acknowledge this. I accept that people may be just fine leaving the elephant in their brain and not paying attention to it and continuing to pretend one thing while they’re doing another. That may be what makes them happy and that may be OK.

My stronger claim would be that policy analysts and social scientists who claim that they understand the social world well enough to make recommendations for changes—they should understand the elephant in the brain. They should have a better idea of hidden motives because they could think about which institutions that we might choose differently to have better outcomes.

And of course I asked:

COWEN: What offends you deep down? You see it out there. What offends you?

And why exactly does it work to invite your date up to “see my etchings”?  And where is “The Great Filter”?  And how much will we identify with our “Em” copies of ourselves?  There is also quantum computing, Robin on movies, and the limits of Effective Altruism.  On top of all that, the first audience question comes from Bryan Caplan.

You should all buy and read Robin’s new book, with Kevin Simler, The Elephant in the Brain: Hidden Motives in Everyday Life.

Toward a Jungian theory of Amish fertility?

At least in the Geauga, Ohio Amish settlements, the decline in fertility followed national fertility trends very closely. Here’s a fun fact: the Amish don’t use most forms of birth control or abortion.

Now, this doesn’t mean Amish fertility fell as low as U.S. general fertility; it simply means that Amish fertility fell as much as U.S. general fertility.

…Cuz what I’m seein’ is that Amish fertility is pretty well correlated with U.S. TFR on the whole.

Scroll down through this Lyman Stone essay to see the graphs of the data (which won’t reproduce for me here, alas).  Here are some pictures in tweet form, if you don’t like scrolling.

Is legal marijuana more potent?

Yes, here is Keith Humphreys from Wonkblog:

Although some people believe prohibiting drugs is what makes their potency increase, the potency of marijuana under legalization has disproved that idea. Potency rises in both legal and illegal markets for the simple reason that it conveys advantages to sellers. More potent drugs have more potential to addict customers, thereby turning them into reliable profit centers.

In other legal drug markets, regulators constrain potency. Legal alcohol beverage concentrations are regulated in a variety of ways, including through different levels of tax for products of different strengths as well as constraints on labeling and place of sale. In most states, for a beverage to be marketed and sold as “beer,” its alcohol content must fall within a specified range. Similarly, if wine is distilled to the point that its alcohol content rises too high, some states require it be sold as spirits (i.e., as “brandy”) and limit its sale locations.

As states have legalized marijuana, they have put no comparable potency restrictions in place, for example capping THC content or levying higher taxes on more potent marijuana strains. Sellers are doing the economic rational thing in response: ramping up potency.

How about the Netherlands?:

The study was conducted in the Netherlands, where marijuana is legally available through “coffee shops.” The researchers examined the level of delta-9-tetrahydrocannabinol (THC), the main intoxicant in marijuana, over a 16-year period. Marijuana potency more than doubled from 8.6 percent in 2000 to 20.3 percent in 2004, which was followed by a surge in the number of people seeking treatment for marijuana-related problems. When potency declined to 15.3 percent THC, marijuana treatment admissions fell thereafter. The researchers estimated that for every 3 percent increase in THC, roughly one more person per 100,000 in the population would seek marijuana use disorder treatment for the first time.

The Dutch findings are relevant to the United States because high THC marijuana products have proliferated in the wake of legalization. The average potency of legal marijuana products sold in the state of Washington, for example, is 20 percent THC, with some products being significantly higher.

I believe that marijuana legalization has moved rather rapidly into being an overrated idea.  To be clear, it is still an idea I favor.  It seems to me wrong and immoral to put people in jail for ingesting substances into their body, or for aiding others in doing so, at least provided fraud is absent in the transaction.  That said, IQ is so often what is truly scarce in society.  And voluntary consumption decisions that lower IQ are not something we should be regarding with equanimity.  Ideally I would like to see government discourage marijuana consumption by using the non-coercive tools at its disposal, for instance by making it harder for marijuana to have a prominent presence in the public sphere, or by discouraging more potent forms of the drug.  How about higher taxes and less public availability for more potent forms of pot, just as in many states beer and stronger forms of alcohol are not always treated equally under the law?

The slowing pace of life expectancy gains since 1950

From Carolina Cardona and David Bishai:

Background

New technological breakthroughs in biomedicine should have made it easier for countries to improve life expectancy at birth (LEB). This paper measures the pace of improvement in the decadal gains of LEB, for the last 60-years adjusting for each country’s starting point of LEB.

Methods

LEB increases over the next 10-years for 139 countries between 1950 and 2009 were regressed on LEB, GDP, total fertility rate, population density, CO2 emissions, and HIV prevalence using country-specific fixed effects and time-dummies. Analysis grouped countries into one-of-four strata: LEB < 51, 51 ≤ LEB < 61, 61 ≤ LEB < 71, and LEB ≥ 71.

Results

The rate of increase of LEB has fallen consistently since 1950 across all strata. Results hold in unadjusted analysis and in the regression-adjusted analysis. LEB decadal gains fell from 4.80 (IQR: 2.98–6.20) years in the 1950s to 2.39 (IQR:1.80–2.80) years in the 2000s for the healthiest countries (LEB ≥ 71). For countries with the lowest LEB (LEB < 51),

decadal gains fell from 7.38 (IQR:4.83–9.25) years in the 1950s to negative 6.82 (IQR: -12.95–1.05) years in the 2000s. Multivariate analysis controlling for HIV prevalence, GDP, and other covariates shows a negative effect of time on LEB decadal gains among all strata.

Conclusions

Contrary to the expectation that advances in health technology and spending would hasten improvements in LEB, we found that the pace-of-growth of LEB has slowed around the world.

Of course in many United States counties, life expectancy is moving backwards these days.

For the pointer I thank the eternal Kevin Lewis.

Ben Thompson on the Amazon consortium and health care

What would make more sense to me is that, having first built an interface for its employees, and then a standardized infrastructure for its health care suppliers, is that Amazon converts the latter into a marketplace where PBMs, insurance administrators, distributors, and pharmacies have to compete to serve employees. And then, once that marketplace is functioning, Amazon will open the floodgates on the demand side, offering that standard interface to every large employer in America…

This is certainly ambitious enough — basically intermediating U.S. employers and the U.S. healthcare industry — but in fact this only sets the stage for the wholesale disruption of American healthcare. First, Amazon could not only open up its standard interface to other large employers, but small-and-medium sized businesses, and even individuals; in this way the Amazon Health Marketplace could aggregate by far the most demand for healthcare.

And to close the piece:

My expectation, then, is not that the Internet methodically disrupts industry after industry in some sort of chronological order, but rather that the entire edifice lasts far longer than technologists think, only to one day collapse far quicker than anyone expected.

The ultimate winners of this shakeout, then, are not only companies that are building businesses predicated on the Internet, but just as importantly, are willing and able to build those businesses with the patience that will be necessary to wait for the old order to collapse, particularly if that collapse happens years or decades after the underlying business models are rotten.

Here is more, and I do hope you are all subscribing to Stratechery, which is one of the very best regular reads, worth the money.

More sectors bad at finding talent (from the comments)

Surgery (and many medical specialties, esp. highly compensated ones) should be on the list of ‘Bad at finding best talent.’ There’s no way to show aptitude for a surgical specialty before medical school, and there is no mechanism for good surgeons to rise to the top, and bad surgeons to be identified and punished. If you make it into a surgical residency, you will succeed, even if you faked your way into med school and your surgical success rate is terrible. There is essentially no mechanisms to make sure aging surgeons learn the newest techniques, and no checks on waning competency. It is only because the training is so long and difficult that it isn’t a complete disaster.

Policing should also be on the list. It’s another job where, like being a surgeon, once you’ve made it into the profession, you have to fail spectacularly to be kicked out. At least half the police officers I know shouldn’t be allowed to carry firearms, much less have the power of life and death over ordinary citizens.

That is from Kevin, based on my earlier post on this question.

Dear Canada: Don’t Ban Paid Blood Plasma Donation

The United States has been called the OPEC of blood plasma because it exports hundreds of millions of dollars worth to other countries. Why does the US dominate the blood plasma industry? Because in the U.S. it’s legal to pay donors which increases supply. Some provinces in Canada have also allowed paid donors but 80% of the blood plasma given to Canadians is imported from the United States and, to make matters worse, some provinces have banned or are considering banning paid donation. A very good letter opposes the ban:

We are professional ethicists in the fields of medical ethics, business ethics, and/or normative ethics, and academic economists who study how incentives and other mechanisms affect individual behaviour. We all share the goal of improving social welfare.

We have strong reservations regarding any Act or legislation (hereafter: “Acts”) that would prohibit compensation for blood plasma donations…….Both the ethical and the economic arguments against a compensatory model for blood plasma for further manufacture into PDMPs are weak. Moreover, significant ethical considerations speak in favour of the compensatory model, and therefore against the Acts.

The letter carefully discusses many of the objections such as that paid donations will drive out unpaid:

The compensatory model leaves open the possibility of donors’ opting out of compensation, or the operation of a parallel non-compensatory model. The United States does just this, and has an approximately 50% higher voluntary, unpaid, per capita blood donation rate than Canada. Germany, Austria, and the Czech Republic, where plasma donors can be compensated, likewise all have higher rates of voluntary, unpaid per capita blood donation than Canada.

Is paid blood plasma less safe?

Dr. Graham Sher, the CEO of Canadian Blood Services, has said, “It is categorically untrue to say, in 2015 or 2016, that plasma-protein products from paid donors are less safe or unsafe. They are not. They are as safe as the products that are manufactured from our unremunerated or unpaid donors.”

The letter is signed by two Nobel Prize winners in economics, Alvin Roth and Vernon Smith, by philosophers like Peter Jaworski, who did most of the heavy lifting, and by experts who have studied incentives and blood donation closely like Nicola Lacetera and Mario Macis. I am also a signatory.

Crime Imprisons and Kills

…the most disadvantaged people have gained the most from the reduction in violent crime.

Though homicide is not a common cause of death for most of the United States population, for African-American men between the ages of 15 and 34 it is the leading cause, which means that any change in the homicide rate has a disproportionate impact on them. The sociologist Michael Friedson and I calculated what the life expectancy would be today for blacks and whites had the homicide rate never shifted from its level in 1991. We found that the national decline in the homicide rate since then has increased the life expectancy of black men by roughly nine months.

…The everyday lived experience of urban poverty has also been transformed. Analyzing rates of violent victimization over time, I found that the poorest Americans today are victimized at about the same rate as the richest Americans were at the start of the 1990s. That means that a poor, unemployed city resident walking the streets of an average city today has about the same chance of being robbed, beaten up, stabbed or shot as a well-off urbanite in 1993. Living in poverty used to mean living with the constant threat of violence. In most of the country, that is no longer true.

That’s Patrick Sharkey writing in the New York Times.

More police on the street is one cause, among many, of lower crime. It’s important in the debate over better policing that we not lose sight of the value of policing. Given the benefits of reduced crime and the cost of police, it’s clear that U.S. cities are under policed (e.g. here and here). We need better policing–including changes in laws–so that we can all be comfortable with more policing.