In my post below I respond to Bryan Caplan's critique of Greg Clark's claim that disease can increase per capita income because it reduces population (i.e., same population has a bigger resource base to work with).¹ I go the route of the two handed economist by suggesting that whether Clark or Caplan is right depends on the details.² Herrick adds in the comments:

Caplan's big claim is that almost anything that persistently raises death rates is likely to persistently reduce output per living worker. It that true?

One possible source of persistent increases in death rates that have no impact on productivity: Many kinds of infectious disease.

I'd welcome medically-informed comments on the topic, but it seems possible for infectious disease (from, say the bad sanitation that Clark emphasizes) to raise the chance of dying any given month without appreciably hurting your productivity most of the time.

Scenario: You get sick for a week or two every couple of years, and if you survive, you go back to being productive. If you don't survive, well then, you're pushing up the death rate.

As I suggest below I think that Caplan is wrong if he wants to claim that productivity is always decreased in direct proportion to the increased disease load (ergo, death rate) of a population. This would prevent the rise in incomes which Clark predicts as the lower productivity of each individual means that the same amount of land can support fewer people at or above subsistence. In A Farewell to Alms Clark reports a rise in incomes after the Black Death, and, amongst native peoples in the New World after Old World diseases ravaged them. Obviously this is one extreme cause: a highly lethal infectious disease which cuts down a large proportion of the population very quickly, and then recedes. The other scenario is a case where there is an endemic infection which reduces physiological fitness across the whole population, reducing lifespan and increasing death rates, but also dampening economic productivity. Then there are cases where there is a wide variance within the population in regards to susceptibility toward infectious agents. This might be more like the first scenario, a large number of people die very quickly, while many others are spared because of some immunity. And so on.

From Darwinian first principles it seems that there should be a large number of pathogens which are infectious but not fatal. Though reducing physiological fitness, they don't knock out their host because to do so would result in their own reduced evolutionary fitness. But hey, Herrick asked for expert opinion. I was actually hoping that someone with medical expertise (e.g., tropical diseases?) would weigh in on that thread, but that didn't happen. So I come to you with open hands and ask you to enlighten....

Update: Greg Clark responds directly to the Caplan critique. As a non-economist I'm more interested in what the empirical historical data says, and what little I know seems to agree with the general thrust of Clark's point.

1 - That sentence should filter out chimpanzee readers since it should be totally incomprehensible to them.

2 - No shit it depends on the details!

Labels: Medicine

One of the interesting findings to come from the recent burst of genome-wide association studies is that many seemingly disparate phenotypes share some genetic pathways. I don't think many people would have a priori considered the possibility of a genetic link between prostate cancer and type II diabetes, yet that's what the data suggest. Other links are somewhat more predictable-- type I diabetes and Crohn's disease both have an autoimmune component, so a genetic link might have been expected. And cornary heart disease and type II diabetes share some envronmental risk factors, so perhaps it's to be expected that similar genetic networks play a role in the two.

These genetic links have all been uncovered by classic reductionist methods-- find the molecular variation that predisposes to disease 1, find the molecular variation that predisposes to disease 2, and compare the two sets. It's simple, and it works.

However, a clever new paper takes a different approach:

Geneticists and epidemiologists often observe that certain hereditary disorders cooccur in individual patients significantly more (or significantly less) frequently than expected, suggesting there is a genetic variation that predisposes its bearer to multiple disorders, or that protects against some disorders while predisposing to others. We suggest that, by using a large number of phenotypic observations about multiple disorders and an appropriate statistical model, we can infer genetic overlaps between phenotypes. Our proof-of-concept analysis of 1.5 million patient records and 161 disorders indicates that disease phenotypes form a highly connected network of strong pairwise correlations. Our modeling approach, under appropriate assumptions, allows us to estimate from these correlations the size of putative genetic overlaps.

This is data mining at its finest.

I'll admit I didn't go through all of the hundreds of pages of supplementary material, but this is fascinating stuff. The authors seem to be particularly interested in autism, which they find correlates with a number of neurological disorders, but also bacterial and viral infections and autoimmune disease:

Our estimated significant overlap between autism and tuberculosis may indicate that both diseases are associated with genetic changes weakening the immune system

Or consider the overlap between bipolar disorder and breast cancer:

Although the competitive genetic overlap between bipolar disorder and female breast cancer has not been reported, there is recent indirect evidence that supports it: a well-established breast cancer drug, tamoxifen, was recently discovered to be effective in treating symptoms of bipolar disorder.

The amount of data generated by the medical community each day is staggering, and as genetic information gets cheaper, it will increasingly be a part of that data. Half the game is knowing what to look for.

Labels: Genetics, Medicine

I realize I'm sort of beating a dead horse by reporting every single high-profile genome-wide association scan (for example), but it's worth pointing out their successes, as there was serious opposition to the HapMap project that laid the groundwork for these studies. So in that spirit, I'll point out this paper, which identifies a common variant in the FTO gene as being associated with obesity:

An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

One of the most important points about genome-wide association studies is that they're (more or less) unbiased-- that is, you don't have to think about which genes could be involved in the phenotype before studying it. Some people consider this a liability, some a blessing. I'm in the latter group, as a strong signal in a genome-wide association can in some cases lead to new candidate genes, new hypotheses and expose interesting biology. This is precisely one of those cases. Here's what's known about the gene identified in this study:

FTO is a gene of unknown function in an unknown pathway that was originally cloned as a result of the identification of a fused-toe (Ft) mutant mouse that results from a 1.6-Mb deletion of mouse chromosome 8. Three genes of unknown function (Fts, Ftm and Fto), along with three members of the Iroquois gene family (Irx3, Irx5, and Irx6 from the IrxB gene cluster), are deleted in Ft mice. The homozygous Ft mouse is embryonically lethal and shows abnormal development, including left/right asymmetry. Heterozygous animals survive and are characterized by fused toes on the forelimbs and thymic hyperplasia but have not been reported to have altered body weight or adiposity. The fused-toe mutant is a poor model for studying the role of altered Fto activity, because multiple genes are deleted. Neither isolated inactivation nor overexpression of Fto has been described.

So essentially, nothing is known about this gene. Thanks to this study, this is unlikely to be the case for long.

Labels: Association, Medicine

One of the most consistent complaints about medical genetics research is that it's great at finding the gene/genes underlying a disease, but finding the gene/genes doesn't necessarily lead to any sort of treatment. The genes for cystic fibrosis and Duchenne muscular dystrophy, for example, were both identified in the late '80s. Both remain uncured. In fact, the genes underlying a large number of so-called "Mendelian" diseases (named because they are essentually due to defects in a single gene, unlike "complex" or "multifactorial" diseases) were identified in a mad rush after the realization in 1980 that disease genes could be found without knowing anything a priori about a disease or its genetics. As far as I know, no treatments have come out of these studies.

But as they say, Rome was not built in a day. If the precise genetic defect underlying a disease can be indentified, someone will find a way to fix it, though it may take many years, new technologies, and a lot of luck. So it's heartening to see a report in this week's Nature on the identification of a compound that may one day be a treatment for disorders caused by nonsense mutations (mutations that cause a truncated protein). From the abstract:

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons.
...
The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Clinical trials have apparently been initiated; this is a story to watch.

Labels: Genetics, Medicine