Physicist, Startup Founder, Blogger, Dad

Tuesday, August 14, 2018

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

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.
Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (Nature Genetics)

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2,3,4,5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.
See also Genomic Prediction: A Hypothetical (Embryo Selection) and Accurate Genomic Prediction Of Human Height.

From the paper:
Using much larger studies and improved algorithms, we set out to revisit the question of whether a GPS can identify subgroups of the population with risk approaching or exceeding that of a mono- genic mutation. We studied five common diseases with major public health impact: CAD, atrial fibrillation, type 2 diabetes, inflamma- tory bowel disease, and breast cancer.

For each of the diseases, we created several candidate GPSs based on summary statistics and imputation from recent large GWASs in participants of primarily European ancestry (Table 1). Specifically, we derived 24 predictors based on a pruning and thresholding method, and 7 additional predictors using the recently described LDPred algorithm13 (Methods, Fig. 1 and Supplementary Tables 1–6). These scores were validated and tested within the UK Biobank, which has aggregated genotype data and extensive phenotypic information on 409,258 participants of British ancestry (average age: 57 years; 55% female)14,15.

We used an initial validation dataset of the 120,280 participants in the UK Biobank phase 1 genotype data release to select the GPSs with the best performance, defined as the maximum area under the receiver-operator curve (AUC). We then assessed the performance in an independent testing dataset comprised of the 288,978 partici- pants in the UK Biobank phase 2 genotype data release. For each disease, the discriminative capacity within the testing dataset was nearly identical to that observed in the validation dataset.

In the talk below @21:45 I discuss prospects for genomic prediction of disease risk.

Wednesday, August 08, 2018

Life and Fate, Before Sunset

This Hollywood oral history tells the story of Richard Linklater's "Before" Trilogy: Before Sunrise, Before Sunset, and Before Midnight. The films appeared 9 years apart, and tell the story of Jesse (Ethan Hawke) and Celine (Julie Delpy) in their 20s, 30s, and 40s. I find the second film to be the most interesting, really a masterpiece of filmmaking (I have a copy on the hard drive of the laptop I write this on :-). The events in Before Sunset take place in real time -- i.e., the story transpires over the run time of the movie, a single afternoon. Shooting it must have been extremely challenging for Delpy and Hawke, and for the crew.

The video above should start at 23:30, and explains how Linklater, Delpy, and Hawke came together to do the sequel. I think that event was, in some sense, the most contingent of those responsible for the trilogy. The first movie made very little money, and hence the idea to make a second, very different film -- about the complexity of life, the passage of time, lost chances -- was neither obvious nor inevitable.

The first movie is about a one night tryst between 20-something travelers, but the second movie takes place a decade later. The protagonists, while still young, have experienced more of life and the second film is richer and more complex, despite taking place over an even shorter period of time. I remember being excited to see it, not so much because of Before Sunrise (which I found entertaining, but not as special), but because of the intriguing premise of two lovers meeting again by chance after losing track of each other for so long.

Here's a scene from Before Sunset: a long take of walking and conversation in beautiful Paris, camera following Hawke and Delpy in a totally naturalistic way.

I hesitate to include this trailer because it's kind of cheesy, but if you're not familiar with the trilogy it explains the premise of the first two films.

The video below is a nice discussion of the trilogy. Just now I learned (thanks, AI!) that Before Sunrise is based on actual events in Linklater's life -- see here for the poignant story of the real life muse for these films.

Richard Linklater also directed Dazed and Confused -- one of the greatest high school movies ever made, and a beautiful evocation of adolescence in late-70s, early-80s America.

Saturday, August 04, 2018

Assassination by Drone

I have been waiting for this to happen:
Reuters: CARACAS - Drones loaded with explosives detonated close to a military event where Venezuelan President Nicolas Maduro was giving a speech on Saturday, but he and top government officials alongside him escaped unharmed from what Information Minister Jorge Rodriguez called an “attack” targeting the leftist leader. Seven National Guard soldiers were injured, Rodriguez added.
See this 2015 post on drone racing and ask yourself how you'd stop one of these drones from getting close to its target.

Countermeasures will be quite difficult, especially if drone operators use sophisticated frequency hopping control.

One doesn't even need pilot operators. The drones can be programmed to fly to a GPS coordinate using an evasive approach.

1. The exact coordinate can be marked by someone in the audience of a public appearance of the target.

2. It would be a formidable challenge even to stop some medium sized drones, each with a few kilo payload, from flying through the windows of the Oval Office (known GPS coordinate; known presence of targets at specific times).

This is still Science Fiction, for now:

Twenty years ago I told a PhD student that a terrorist -- willing to die and able to fly an airplane -- could probably take out the White House. After 9/11 he reminded me that I had identified this hole in the system well in advance. It's the same thing here with small and medium size drones. They are accessible to non-state actors with limited resources, and very difficult to defeat, even for state security.

Barista Bots

Still think low-skill immigration is a good idea?

If you accept the thesis that automation is a threat to low-skill employment, then you should be willing to reconsider the long term cost-benefit analysis of low-skill immigration.

Thursday, August 02, 2018

Arnold: The Will to Power

I don't know whether Arnold ever read Nietzsche, but he certainly developed the Will to Power early in life. I quite like the video above -- I even made my kids watch it :-)

When I was in high school I came across his book Arnold: The Education of a Bodybuilder, a combination autobiography and training manual published in 1977. I found a copy in the remainder section of the book store and bought it for a few dollars. The most interesting part of the book is the description of his early life in Austria and his introduction to weightlifting and bodybuilding. I highly recommend it to anyone interested in golden age bodybuilding, the early development of physical training, or the psychology of human drive and high achievement. Young Arnold displays a kind of unbridled and un-ironic egoism that can no longer be expressed without shame in today's feminized society.

Chapter 2: Before long, people began looking at me as a special person. Partly this was the result of my own changing attitude about myself. I was growing, getting bigger, gaining confidence. I was given consideration I had never received before; it was as though I were the son of a millionaire. I'd walk into a room at school and my classmates would offer me food or ask if they could help me with my homework. Even my teachers treated me differently. Especially after I started winning trophies in the weight-lifting contests I entered.

This strange new attitude toward me had an incredible effect on my ego. It supplied me with something I had been craving. I'm not sure why I had this need for special attention. Perhaps it was because I had an older brother who'd received more than his share of attention from our father. Whatever the reason, I had a strong desire to be noticed, to be praised. I basked in this new flood of attention. I turned even negative responses to my own satisfaction.

I'm convinced most of the people I knew didn't really understand what I was doing at all. They looked at me as a novelty, a freak. ...

"Why did you have to pick the least-favorite sport in Austria?" they always asked. It was true. We had only twenty or thirty bodybuilders in the entire country. I couldn't come up with an answer. I didn't know. It had been instinctive. I had just fallen in love with it. I loved the feeling of the gym, of working out, of having muscles all over.

Now, looking back, I can analyze it more clearly. My total involvement had a lot to do with the discipline, the individualism, and the utter integrity of bodybuilding. But at the time it was a mystery even to me. Bodybuilding did have its rewards, but they were relatively small. I wasn't competing yet, so my gratification had to come from other areas. In the summer at the lake I could surprise everyone by showing up with a different body. They'd say, "Jesus, Arnold, you grew again. When are you going to stop?"

"Never," I'd tell them. We'd all laugh. They thought it amusing. But I meant it.


The strangest thing was how my new body struck girls. There were a certain number of girls who were knocked out by it and a certain number who found it repulsive. There was absolutely no in-between. It seemed cut and dried. I'd hear their comments in the hallway at lunchtime, on the street, or at the lake. "I don't like it. He's weird—all those muscles give me the creeps." Or, "I love the way Arnold looks—so big and powerful. It's like sculpture. That's how a man should look."

These reactions gave me added motivation to continue building my body. I wanted to get bigger so I could really impress the girls who liked it and upset the others even more. Not that girls were my main reason for training. Far from it. But they added incentive and I figured as long as I was getting this attention from them I might as well use it. I had fun. I could tell if a girl was repelled by my size. And when I'd catch her looking at me in disbelief, I would casually raise my arm, flex my bicep, and watch her cringe. It was always good for a laugh. ...
Arnold, age 17 or 18:

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