Text

Physicist, Startup Founder, Blogger, Dad

Sunday, October 14, 2018

Nature News on Polygenic Genomic Prediction


See also Population-wide Genomic Prediction of Health Risks.
The approach to predictive medicine that is taking genomics research by storm (Nature News)

Polygenic risk scores represent a giant leap for gene-based diagnostic tests. Here’s why they’re still so controversial.

... Supporters say that polygenic scores could be the next great stride in genomic medicine, but the approach has generated considerable debate. Some research presents ethical quandaries as to how the scores might be used: for example, in predicting academic performance. Critics also worry about how people will interpret the complex and sometimes equivocal information that emerges from the tests. And because leading biobanks lack ethnic and geographic diversity, the current crop of genetic screening tools might have predictive power only for the populations represented in the databases.

“Most people are keen to have a decent debate about this, because it raises all sorts of logistical and social and ethical issues,” says Mark McCarthy, a geneticist at the University of Oxford, UK. Even so, polygenic scores are racing to the clinic and are already being offered to consumers by at least one US company.

Peter Visscher, a geneticist at the University of Queensland, Australia, who pioneered the methods that underlie the trend, is broadly optimistic about the approach, but is still surprised by the speed of progress. “I’m absolutely convinced this is going to come sooner than we think,” he says. ...
Below are some remarks from earlier posts. Population-wide Genomic Prediction of Health Risks:
I estimate that within a year or so there will be more than 10 good genomic predictors covering very significant disease risks, ranging from heart disease to diabetes to hypothyroidism to various cancers. These predictors will be able to identify the, e.g., few percent of the population that are outliers in risk -- for example, have 5x or 10x the normal likelihood of getting the disease at some point in their lives. Risk predictions can be made at birth (or before! or in adulthood), and preventative care allocated appropriately. All of these risk scores can be computed using a genotype read from an inexpensive (< $50 per person) array that probes ~1M or so common SNPs.

Genomic Prediction of disease risk using polygenic scores:
It seems to me we are just at the tipping point -- soon it will be widely understood that with large enough data sets we can predict complex traits and complex disease risk from genotype, capturing most of the estimated heritable variance. People will forget that many "experts" doubted this was possible -- the term missing heritability will gradually disappear.

In just a few years genotyping will start to become "standard of care" in many health systems. In 5 years there will be ~100M genotypes in storage (vs ~20M now), a large fraction available for scientific analysis.

Saturday, October 13, 2018

Physics as a Strange Attractor


Almost every student who attends a decent high school will be exposed to Special Relativity. Their science/physics teacher may not really understand it very well, may do a terrible job trying to explain it. But the kid will have to read a textbook discussion and (in the internet age) can easily find more with a simple search.

Wikipedia entry on Special Relativity:
In Albert Einstein's original pedagogical treatment, it is based on two postulates:

1. The laws of physics are invariant (i.e., identical) in all inertial systems (i.e., non-accelerating frames of reference).

2. The speed of light in a vacuum is the same for all observers, regardless of the motion of the light source.
What happens next depends, of course, on the kid. I posit that above a certain (perhaps very high) threshold in g and in intellectual curiosity, almost everyone will invest some hours to think about this particular topic. Special Relativity is fundamental to our understanding of space and time and causality, and has a certain intellectual and cultural glamour. Furthermore, it is amazing that a simple empirical observation like 2 above has such deep and significant consequences. A bright individual who invests those few hours is likely to come away with an appreciation of the beauty and power of physics and the mathematical approach to natural science.

I suspect that Special Relativity, because it is easy to introduce (no mathematics beyond algebra is required), yet deep and beautiful and counterintuitive, stimulates many people of high ability to become interested in physics.

So what does it mean when you meet an educated adult who does not understand Special Relativity? Does it suggest an upper bound (albeit perhaps very high) on a combination of their cognitive ability and intellectual curiosity? I mention curiosity (perhaps better to say interest in first principles or deep knowledge) because of course some (how many?) people of high ability will simply not be interested in the topic. However, as ability level increases the amount of effort necessary to learn and retain the information decreases. So someone with very off-scale ability would have to be quite incurious not to absorb and retain some basic understanding of relativity, if only from school days.

Years ago I was discussing a particle accelerator facility with a distinguished (internationally renowned) engineering professor. I mentioned that the particles in the beam would reach a certain fraction of the speed of light. He asked me why they could not reach or surpass the speed of light. It became obvious that he had essentially zero understanding of Special Relativity, and I was shocked.

We could go a bit further. General Relativity (also an invention of Einstein) describes the dynamics of spacetime (sound interesting?), and is connected to topics in popular culture such as black holes, time travel, wormholes, galactic empires, etc. General Relativity is far more complex than Special Relativity, but can be introduced to someone who has a good grasp of multivariable calculus. For example, Dirac's lecture notes on the subject provide a pedagogical introduction in only 62 pages. Yet what fraction of adults have even a modest grasp of this topic? Perhaps one in ten or a hundred thousand at best.

What is the cognitive threshold to learn Special or General Relativity? What is the cognitive threshold to remember something about it ten or twenty years later? Is the cognitive threshold higher, or the threshold in intellectual curiosity required to ponder such things?

See also One hundred thousand brains and Quantum GDP.

Thursday, October 11, 2018

Population-wide Genomic Prediction of Health Risks


The UK is ahead of the US in the application of genomics in clinical practice. Part of this is due to their leadership in projects like the UK Biobank (500k genomes with extensive biomedical phenotyping), and part is due to having a single-payer system that can adopt obviously beneficial (and cost-beneficial) practices after some detailed study. Former Prime Minister David Cameron's son has a rare genetic disease, which contributed to his strong support of genomics research in the UK. The decentralized (broken) US health care system, which does not focus on quality of outcome, is having a hard time with no-brainer decisions like making inexpensive genotyping Standard of Care. Will insurance reimburse?

I estimate that within a year or so there will be more than 10 good genomic predictors covering very significant disease risks, ranging from heart disease to diabetes to hypothyroidism to various cancers. These predictors will be able to identify the, e.g., few percent of the population that are outliers in risk -- for example, have 5x or 10x the normal likelihood of getting the disease at some point in their lives. Risk predictions can be made at birth (or before! or in adulthood), and preventative care allocated appropriately. All of these risk scores can be computed using a genotype read from an inexpensive (< $50 per person) array that probes ~1M or so common SNPs.

In technical papers my research group anticipated years ago that even very complex traits would be predictable once a data threshold was crossed. The phenomenon is related to what physicists refer to as a phase transition in algorithm performance. The rapid appearance now of practically useful risk predictors for disease is one anticipated consequence of this phase transition. Medicine in well-functioning health care systems will be transformed over the next 5 years or so.

Test could predict risk of future heart disease for just £40 (Guardian)

Genomic Risk Score test is cheap enough to allow population-wide screening of children, researchers believe

A one-off genetic test costing less than £40 can show if a person is born with a predisposition to heart disease.

The Genomic Risk Score (GRS) test is cheap enough to allow population-wide screening of children, researchers believe. Medical and lifestyle interventions could then be employed to reduce the chances of those most at risk of suffering heart attacks in adulthood.

A study found that participants with a GRS in the top 20% were more than four times more likely to develop coronary heart disease than those with scores in the bottom 20%. Many in the “at risk” category lacked the usual heart disease indicators, such as high cholesterol and blood pressure.

Senior author Sir Nilesh Samani, the professor of cardiology at the University of Leicester and medical director of the British Heart Foundation charity, said: “At the moment, we assess people for their risk of coronary heart disease in their 40s through NHS health checks. But we know this is imprecise and also that coronary heart disease starts much earlier, several decades before symptoms develop.

“Therefore, if we are going to do true prevention, we need to identify those at increased risk much earlier. This study shows that the GRS can now identify such individuals.

“Applying it could provide a most cost-effective way of preventing the enormous burden of coronary heart disease, by helping doctors select patients who would most benefit from interventions.”

Coronary heart disease is the leading cause of death worldwide and claims 66,000 lives each year in the UK. Healthcare costs related to heart and circulatory diseases in the UK are estimated at £9bn per year. ...
Related posts:

Advances in Genomic Prediction

Genomic Prediction of disease risk using polygenic scores (Nature Genetics)

Genomic Prediction: A Hypothetical (Embryo Selection), Part 2

Wednesday, October 10, 2018

Well done, tovarishch




I thought Khabib's grappling would dominate McGregor's striking. Tony Ferguson would have given him a tougher fight.

The finish was not a choke -- probably a jaw lock. It seems that Conor almost taps, stops, then realizes his jaw is in danger (or just gives up, which is part of his MO) and taps.




Friday, October 05, 2018

Advances in Genomic Prediction

Apologies, I've been super busy lately. Below are some links of interest.

Genomic prediction of cognitive traits in childhood and adolescence (Plomin): predictor reaches correlation of ~0.33 for cognitive ability and ~0.4 for Educational Attainment.

Machine Learning to Predict Osteoporotic Fracture Risk from Genotypes. Another potentially clinically useful result. I'd guess we'll have >10 good polygenic disease risk predictors within a year.

Genomic Prediction and IVF in WSJ: Discusses eye color as well as our results.

New DNA Tool Predicts Height, Shows Promise for Serious Illness Assessment. Includes podcast interview with me.

Register for online discussion of our height / L1 optimization paper, hosted by the journal GENETICS. Thursday, October 25, 2018 12:00-1:00PM (ET)

Interview on Airtalk
(KPCC Los Angeles NPR show).


Figure from the bone fracture risk paper linked above. It appears that individuals with polygenic scores in the bottom few percent (highest risk) are ~4 times as likely to suffer a hip or other major fracture.


Blog Archive

Labels