Monday, August 29, 2016

A2AD fait accompli?



As I mentioned previously, Australian strategists are a good source of analysis on China-US defense issues in the western Pacific because they are caught in the middle and have to think realistically about the situation.

@3:30 min: A2AD by DF21 / DF26 ASBM a fait accompli? 9 dash line to become a reality? Is containment broken?

See earlier post The Pivot and American Statecraft in Asia.

I linked to the report below some time ago.
China’s Constellation of Yaogan Satellites & the Anti-Ship Ballistic Missile – An Update

Professor S. Chandrashekar and Professor Soma Perumal
International Strategic & Security Studies Programme (ISSSP)
National Institute of Advanced Studies (NIAS)
December 2013

With the recent launch of the Yaogan 19 satellite China has in place an advanced space capability to identify, locate and track an Aircraft Carrier Group (ACG) on the high seas. This space capability is an important component of an Anti-Ship Ballistic Missile (ASBM) System that China has set up.

The current 19 satellite constellation consists of ELINT satellites, satellites carrying Synthetic Aperture Radar (SAR) sensors as well as satellites carrying optical imaging sensors. Based on the orbit characteristics, their local time of equatorial crossing and other related parameters, these satellites can be grouped into different categories that perform the various functions for identifying, locating and tracking the ACG.

Yaogan 9 (Yaogan 9A, 9B, 9C), Yaogan (16A, 16B, 16C) and Yaogan 17 (17A, 17B, 17C) are the three clusters that are equipped with ELINT sensors that provide broad area surveillance over the Oceans. With a coverage radius of about 3500 Km, they provide the first coarse fix for identifying and locating an ACG in the Pacific Ocean.

Yaogan 13, Yaogan 10, Yaogan 18 and Yaogan 14 are the satellites carrying a SAR sensor. With Local times of crossing of 02 00, 06 00, 10 00 and 14 00 hours and a resolution of 1 to 3 m , they provide all weather as well as day and night imaging capabilities over the regions of interest.

Yaogan 11, Yaogan 4, Yaogan 2 and Yaogan 7 constitute the high resolution optical satellites in the current constellation. The sensors they carry may have resolutions of between 1 to 3 m.

... 
The analysis and the simulation results suggest that China has in place an operational ASBM system that can identify, locate, track and destroy an Aircraft Carrier in the Pacific Ocean.

This seems to be an important component of a larger Chinese Access and Area Denial Strategy focused around a conflict over Taiwan.
Over the summer I bumped into a micro-satellite startup guy at the Googleplex and we got onto the subject of imaging aircraft carriers from space. He thought a carrier group would be easy to image and couldn't possibly survive a serious conflict in the Pacific.

Sunday, August 28, 2016

Geoffrey Miller on Virtue Signalling (audio + slides)



This talk was given at the meeting Effective Altruism Global 2016. Includes a good warning about IQ signaling and some advice on how to market a movement to neurotypicals. Slides.


More Geoffrey Miller :-)

Friday, August 26, 2016

GWAS: Multiple Loci Influencing Normal Human Facial Morphology


These are not surprising results, given that identical twins raised apart tend to have nearly identical facial morphology. It's implausible that most of this heritability is due to rare variants. If large GWASes would take photos and video of individuals in the study, genomic prediction of facial morphology could advance dramatically using face recognition algorithms.

See also HLI and genomic prediction of facial morphology  (source of image above of Craig Venter).
Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

http://dx.doi.org/10.1371/journal.pgen.1006149

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Wednesday, August 24, 2016

Tyler Cowen on Efficient Markets (video)



Tyler Cowen explains the basics of the Efficient Market Hypothesis. For a deeper exploration, see Tyler Cowen and rationality, which links to his paper How economists think about rationality.
Tyler Cowen and rationality [my comments]: ... The excerpt below deals with rationality in finance theory and strong and weak versions of efficient markets. I believe the weak version; the strong version is nonsense. (See, e.g, here for a discussion of limits to arbitrage that permit long lasting financial bubbles. In other words, capital markets are demonstrably far from perfect, as defined below by Cowen.)

Although you might think the strong version of EMH is only important to traders and finance specialists, it is also very much related to the idea that markets are good optimizers of resource allocation for society. Do markets accurately reflect the "fundamental value of corporations"? See related discussion here.

...

As you can tell from my comments, I do not believe there is any unique basis for "rationality" in economics. Humans are flawed information processing units produced by the random vagaries of evolution. Not only are we different from each other, but these differences arise both from genes and the individual paths taken through life. Can a complex system comprised of such creatures be modeled through simple equations describing a few coarse grained variables? In some rare cases, perhaps yes, but in most cases, I would guess no. Finance theory already adopts this perspective in insisting on a stochastic (random) component in any model of security prices. Over sufficiently long timescales even the properties of the random component are not constant! (Hence, stochastic volatility, etc.)

Tuesday, August 23, 2016

Bayesian large-scale multiple regression with summary statistics from genome-wide association studies

This is an interesting idea, which has also been advocated to me over the years by my collaborator Carson Chow (blog). I'm optimistic that we're entering an era of large data sets that can be analyzed in situ using more sophisticated algorithms than simple regression. However, it will always be useful to have a better method for combining multiple data sets using only aggregate statistics.

Xiang Zhu's slides.
Bayesian large-scale multiple regression with summary statistics from genome-wide association studies

Xiang Zhu, Matthew Stephens
doi: http://dx.doi.org/10.1101/042457

Bayesian methods for large-scale multiple regression provide attractive approaches to the analysis of genome-wide association studies (GWAS). For example, they can estimate heritability of complex traits, allowing for both polygenic and sparse models; and by incorporating external genomic data into the priors they can increase power and yield new biological insights. However, these methods require access to individual genotypes and phenotypes, which are often not easily available. Here we provide a framework for performing these analyses without individual-level data. Specifically, we introduce a "Regression with Summary Statistics" (RSS) likelihood, which relates the multiple regression coefficients to univariate regression results that are often easily available. The RSS likelihood requires estimates of correlations among covariates (SNPs), which also can be obtained from public databases. We perform Bayesian multiple regression analysis by combining the RSS likelihood with previously-proposed prior distributions, sampling posteriors by Markov chain Monte Carlo. In a wide range of simulations RSS performs similarly to analyses using the individual data, both for estimating heritability and detecting associations. We apply RSS to a GWAS of human height that contains 253,288 individuals typed at 1.06 million SNPs, for which analyses of individual-level data are practically impossible. Estimates of heritability (52%) are consistent with, but more precise, than previous results using subsets of these data. We also identify many previously-unreported loci that show evidence for association with height in our analyses. Software implementing RSS is available at https://github.com/stephenslab/rss.

Monday, August 22, 2016

Wikileaks, Julian Assange, and an October(?) Surprise



In recent interviews Julian Assange more or less claims to have the goods on Hillary. If I had to guess, I suppose he might have email traffic showing that she lied to congress, for example in the exchange above with Rand Paul, or perhaps in some of her answers to questions about her private email server. The most impactful time to release this information is probably just before one of the debates.
Paul: "It’s been in news reports that ships have been leaving from Libya and that they may have weapons. And what I’d like to know is, that [CIA] annex that was close by [the State Department facility], were they involved with procuring, buying, selling, obtaining weapons, and were any of these weapons being transferred to other countries? Any countries, Turkey included?"

Clinton: “I don’t know. I don’t have any information on that.”
If we lived in a country where rule of law applied, there might be serious consequences for this sort of thing. In the 21st century USA, we'll be lucky if any mainstream media outlets cover the story ;-) The NYTimes will probably just blame the Russians.

Wednesday, August 17, 2016

The Pivot and American Statecraft in Asia

Hugh White, Professor of Strategic Studies at the Australian National University, critiques the Obama administration's so-called pivot to Asia. Australian strategists are a good source of analysis on this issue because they are caught in the middle and have to think realistically about the situation.

Whenever I see a book or article on this topic I quickly search for terms like DF-21, ASBM, ASCM, cruise missiles, satellite imaging, submarines, etc. The discussion cannot be serious or deep without an understanding of current military and technological capabilities of both sides. (See High V, Low M.)
Book review: 'The Pivot: The Future of American Statecraft in Asia', by Kurt Campbell: As Assistant Secretary of State for Asia in Barack Obama's first term, Kurt Campbell has a respectable claim to being the principal architect of the president's Pivot to Asia. Not surprisingly, then, his new book The Pivot: The Future of American Statecraft in Asia argues that the Pivot is the right policy for America in Asia over coming years, and explains how it should be elaborated and extended under the next president.

... Washington has never clearly identified or analysed the problem which the Pivot is supposed to solve, and The Pivot doesn't either. And yet there is no mystery here. America's problem in Asia today is that China seeks to take its place as the primary power in Asia, and the shift in relative power between the two countries over recent decades makes China's challenge very formidable indeed. This simple fact must be at the centre of any serious analysis of America's policy options in Asia.

The Pivot mentions China a lot, but does not plainly acknowledge the centrality of its challenge to America's predicament in Asia today, and nowhere seriously assesses the power and ambition that drive China's challenge. Nor is the book clear about America's objectives. In places it says America's aims include preventing Asia falling under someone else's hegemony, but elsewhere that the Pivot is all about preserving Asia's geopolitical 'operating system', by which it plainly means preserving the status quo based on US primacy.

Thus the book, like the policy itself, is based on evasions about both China's and America's aims, and therefore avoids acknowledging how directly those aims conflict, and how stark and serious the resulting confrontation between them has already become.

... The practical steps taken under the Pivot have always been far too modest to meet the challenge America faces in Asia. Indeed, it is hard to imagine that they were ever intended to have more than a symbolic effect. The Pivot's architects apparently assumed that a merely symbolic reassertion of US power and resolve would be enough to make China back off and abandon its challenge. China's assertive posture in the East and South China Seas today is strong evidence that they were wrong.

... In particular, The Pivot has nothing to say about the most important single question facing America in Asia today: is it willing to go to war with China to preserve US primacy? This question, more than anything else, will determine the shape of future Asian order and America's role in it. China's recent conduct strongly suggests that it will only abandon its challenge to American primacy if it is really convinced that the answer is 'yes'. But nothing Beijing has seen or heard from Washington in recent years has convinced it of that, which is why it has been acting so boldly. Unless that changes, the chances of facing down Beijing's challenge are very low.

That will not change until an American president is willing to stand up and explain to America's people why US primacy in Asia is so important to them that they should be willing to go to war with China to preserve it. The answer to that question must encompass the fact that China is a nuclear-armed power with the capacity to destroy US cities. This is an issue which The Pivot entirely avoids. I found no substantive reference to China's nuclear forces in the entire book, nor to extended nuclear deterrence as the foundation of America's key alliances, and hence to its position in Asia. No analysis that evades these hard questions can address the future of America's Asia strategy effectively.

So Kurt Campbell's new book reinforces the impression that important elements of America's foreign policy establishment still haven't begun either to take China's rise seriously or to consider the momentous choices America faces in response to it. Until that changes, America's response to China is unlikely to become much more effective than it has been for the five years since Barack Obama launched the Pivot in Canberra. And so it becomes more and more likely that American power in Asia will continue to dwindle.
See also Red Star over the Pacific and The Thucydides Trap.

I added the following in the comments. These questions of military/technological capability stand prior to the prattle of diplomats, policy analysts, or political scientists. Perhaps just as crucial is whether top US and Chinese leadership share the same beliefs on these issues.
It's hard to war game a US-China pacific conflict, even a conventional one. How long before the US surface fleet is destroyed by ASBM/ASCM? How long until forward bases are? How long until US has to strike at targets on the mainland? How long do satellites survive? How long before the conflict goes nuclear? I wonder whether anyone knows the answers to these questions with high confidence -- even very basic ones, like how well asymmetric threats like ASBM/ASCM will perform under realistic conditions. These systems have never been tested in battle.

The stakes are so high that China can just continue to establish "facts on the ground" (like building new island bases), with some confidence that the US will hesitate to escalate. If, for example, both sides secretly believe (at the highest levels; seems that Xi is behaving as if he might) that ASBM/ASCM are very effective, then sailing a carrier group through the South China Sea becomes an act of symbolism with meaning only to those that are not in the know.
This Aug 2016 RAND report delves into some of the relevant issues (see Appendix A, p.75). But it is not clear whether the 2025 or 2015 scenarios explored will be more realistic over the next few years. A weakness of the report is that it assumes US forces will undertake large scale conventional attack on the Chinese mainland (referred to as Air Sea Battle by US planners) relatively early in the conflict, without fear of nuclear retaliation. A real decision maker could not confidently make that assumption, PRC "no first use" declaration notwithstanding.

See also Future Warfare in the Western Pacific (International Security, Summer 2016) for a detailed analysis of A2AD capability, potentially practiced by both sides. I disagree with the authors' claim that the effectiveness of A2AD in 2040 will be limited to horizon distances (they assume all satellites have been destroyed). The authors neglect the possibility of large numbers of stealthy drone radar platforms (or micro-satellites) which are hard to detect until they activate to provide targeting data to incoming missiles.

This article by Peter Lee gives a realistic summary of the situation, including the role of nuclear weapons. As a journalist, Lee is not under the same political restrictions as RAND or others funded by the US military / defense industry. The survivability of the surface fleet (=aircraft carriers) and the escalatory nature of what is known as Air Sea Battle (=ASB) are both highly sensitive topics.

Sunday, August 14, 2016

Cheng Li on elite Chinese politics (Sinica podcast)

Excellent podcast interview with Cheng Li of Brookings. Li has both a long historical perspective on Chinese politics (having lived through the Cultural Revolution) and a detailed understanding of current developments. He addresses topics such as technocracy, rule of law, Xi Jinping, corruption, princelings vs grassroots party members, etc.
Sinica podcast: One of the most prominent international scholars of elite Chinese politics speaks about the past, present and future of factionalism, reform and technocracy in China and the nation's direction under Xi Jinping.
Li grew up in Shanghai during the Cultural Revolution. In 1985 he came to the United States, where he received a master's in Asian studies from the University of California, Berkeley and a doctorate in political science from Princeton University. From 1993 to 1995, he worked in China as a fellow sponsored by the Institute of Current World Affairs in the U.S., observing grassroots changes in his native country. Based on this experience, he published a nationally acclaimed book, "Rediscovering China: Dynamics and Dilemmas of Reform" (1997).

Li is also the author or the editor of numerous books, including "China’s Leaders: The New Generation" (2001), "Bridging Minds Across the Pacific: The Sino-U.S. Educational Exchange 1978-2003" (2005), "China’s Changing Political Landscape: Prospects for Democracy" (2008), "China’s Emerging Middle Class: Beyond Economic Transformation" (2010), "The Road to Zhongnanhai: High-Level Leadership Groups on the Eve of the 18th Party Congress" (in Chinese, 2012), "The Political Mapping of China’s Tobacco Industry and Anti-Smoking Campaign" (2012), "China's Political Development: Chinese and American Perspectives" (2014), "Chinese Politics in the Xi Jinping Era: Reassessing Collective Leadership" (2016), and "The Power of Ideas: The Rising Influence of Thinkers and Think Tanks in China" (forthcoming). He is currently completing a book manuscript with the working title "Middle Class Shanghai: Pioneering China’s Global Integration." He is the principal editor of the Thornton Center Chinese Thinkers Series published by the Brookings Institution Press.

Half of all jobs (> $60k/y) coding related?

In the future there will be two kinds of jobs. Workers will either

Tell computers what to do    

or

Be told by computers what to do





See this jobs report, based on BLS statistics and analysis of 26 million job postings scraped from job boards, newspapers, and other online sources in 2015.
Coding jobs represent a large and growing part of the job market. There were nearly 7 million job openings in the U.S. last year for roles requiring coding skills. This represents 20% of the total market for career-track jobs that pay $15 an hour or more. Jobs with coding skills are projected to grow 12% faster than the job market overall in the next 10 years. IT jobs are expected to grow even more rapidly: 25% faster than the overall market.1

Programming skills are in demand across a range of industries. Half of all programming openings are in Finance, Manufacturing, Health Care, and other sectors outside of the technology industry.

...

Jobs valuing coding skills pay $22,000 per year more, on average, than jobs that don’t: $84,000 vs $62,000 per year. The value of these skills is striking and, for students looking to increase their potential income, few other skills open the door to as many well-paying careers. Slicing the data another way, 49% of the jobs in the top wage quartile (>$58,000/yr) value coding skills.

...

We define coding jobs as those in any occupation where knowing how to write computer code makes someone a stronger candidate and where employers commonly request coding skills in job postings. In some cases, coding is a prerequisite skill for the role, such as for Database Administrators. In other cases, such as Graphic Designers, knowing how to code may not be required in all cases, but job seekers with relevant programming skills will typically have an advantage.
See also The Butlerian Jihad and Darwin among the Machines.

Friday, August 12, 2016

Greg Cochran on James Miller's Future Strategist podcast



James Miller interviews Greg Cochran on a variety of topics.

Some comments on the early part of the interview (you might need to listen to it to make sense of what I write below):

1. The prediction I've made about the consequences of additive genetic variance in intelligence is not that we'll be able to realize +30 SDs of cognitive ability. That would only be true if we could ignore pleiotropy, nonlinear corrections to the additive approximation, etc. What I claim is that because there are +30 SDs up for grabs in the first order approximation, it seems likely that at least a chunk of this will be realizable, leading to geniuses beyond those that have existed so far in human history (this is the actual claim). To doubt this conclusion one would have to argue that even, say, +8 or +10 SDs out of 30 are unrealizable, which is hard to believe since we have examples of healthy and robust individuals who are in the +6 or +7 range. (These numbers are poorly defined since the normal distribution fails to apply in the tails.)

### I could make further, more technical, arguments that originate from the fact that the genomic space is very high dimensional. These suggest that, given healthy/robust examples at +X, it is very unlikely that there is NO path in the high dimensional space to a phenotype value greater than X while holding "robustness" relatively fixed. ###

2. Greg comments on whether super smart people can have "normal" personalities. This is obviously not necessary for them to be viable contributors to civilization (and even less of an issue in a future civilization where everyone is quite a bit smarter on average). He posits that von Neumann might have been radically strange, but able to emulate an ordinary person when necessary. (The joke is that he was actually a Martian pretending to be human.) My impression from reading Ulam's autobiography, Adventures of a Mathematician (see also here), is that von Neumann was actually not that strange by the standards of mathematicians -- he was sociable, had a good sense of humor, enjoyed interactions with others and with his family. He and Ulam were close and spent a lot of time together. I suspect Ulam's portrait of vN is reasonably accurate.

3. The University of Chicago conference on genetics and behavior Greg mentions, which was hosted in James Heckman's institute, is described here, here, and here (videos).


### A masochist in the comments asked for the actual argument, so here it is: ###
Here's a simple example which I think conveys the basic idea.

Suppose you have 10k variants and that individuals with 5.5k or more + variants are at the limit of cognitive ability yet seen in history (i.e., at the one in a million or billion or whatever level). Now suppose that each of the 10k + variants comes with some deleterious effect on some other trait(s) like general health, mental stability, etc. (This is actually too pessimistic -- some will actually come with positive effects!) These deleterious effects are not uniform over the 10k variants -- for some fixed number of + variants (i.e., 5.5k) there are many different individuals with different levels of overall health/robustness.

Let the number of distinct genotypes that lead to (nearly) "maximal historical" cognitive ability be n = (number of ways to distribute 5.5k +'s over 10k variants); this is a huge number. Now, we know of many actual examples of historical geniuses who were relatively healthy and robust. The probability that these specific individuals achieved the *minimum* level of negative or deleterious effects over all n possibilities is vanishingly small. But that means that there are genotypes with *more* than 5.5k + variants at the same level of general robustness. These correspond to individuals who are healthy/robust but have greater cognitive ability than any historical genius.

You can make this argument fully realistic by dropping the assumption that + effect sizes on cognitive ability are uniform, that effects on different traits are completely additive, etc. The point is that there are so many genotypes that realize [cognitive ability ~ historical max], that the ones produced so far are unlikely to maximize overall health/robustness given that constraint. But that means there are other genotypes (off the surface of constraint) with even higher cognitive ability, yet still healthy and robust.

Thursday, August 11, 2016

We Are Nowhere Close to the Limits of Athletic Performance (Nautilus Magazine)


This is in the special Sports issue -- just in time for Rio :-)
We Are Nowhere Close to the Limits of Athletic Performance

For many years I lived in Eugene, Oregon, also known as “track-town USA” for its long tradition in track and field. Each summer high-profile meets like the United States National Championships or Olympic Trials would bring world-class competitors to the University of Oregon’s Hayward Field. It was exciting to bump into great athletes at the local cafe or ice cream shop, or even find myself lifting weights or running on a track next to them. One morning I was shocked to be passed as if standing still by a woman running 400-meter repeats. Her training pace was as fast as I could run a flat out sprint over a much shorter distance.

The simple fact was that she was an extreme outlier, and I wasn’t. Athletic performance follows a normal distribution, like many other quantities in nature. That means that the number of people capable of exceptional performance falls off exponentially as performance levels increase. While an 11-second 100-meter can win a high school student the league or district championship, a good state champion runs sub-11, and among 100 state champions only a few have any hope of running near 10 seconds.

... Freeman Dyson speculated that, one day, humans would use genetic technologies to modify themselves for space exploration—making themselves more resistant to radiation, vacuum, and zero gravity, perhaps even able to extract energy directly from sunlight. Insertion of genes from entirely different species, like photosynthetic plant genes, brings a whole new meaning to the term GMO: Speciation seems a definite possibility.

Human athletic ability might follow a similar trajectory. The nature of athletes, and the sports they compete in, are going to change due to new genomic technology. Will ordinary people lose interest? History suggests that they won’t: We love to marvel at exceptional, unimaginable ability. Lebron and Kobe and Shaq and Bolt all stimulated interest in their sports. The most popular spectator sport of 2100 might be cage fights between 8-foot-tall titans capable of balletic spinning head kicks and intricate jiu-jitsu moves. Or, just a really, really fast 100m sprint. No doping required.



Wednesday, August 10, 2016

Genetic Engineering Will Change Everything Forever (video)



This video is one of the best introductions to the coming genomic revolution that I have seen.

It emphasizes breakthroughs like CRISPR that will make gene editing simple, safe, and effective. However, it spends little time explaining how scientists will decipher genetic architectures (i.e., using big data sets and machine learning) in order understand which edits to make.

I might also quibble with the claim that a DNA edit is a permanent change to the human gene pool. If we don't like it we can always edit back to the original...

Sunday, August 07, 2016

Podcast: Clay Shirky on tech and the internet in China

Highly recommended. Unfortunately I can't embed the podcast here so you'll have to click through.
In this episode of Sinica, Clay Shirky, the author of Here Comes Everybody who has written about the internet and its effects on society since the 1990s, joins Kaiser and Jeremy to discuss the strengths and weaknesses of China’s tech industry and the extraordinary advances the nation has made in the online world.

The hour-long conversation delves into the details and big-picture phenomena driving the globe’s largest internet market, and includes an analysis of Xiaomi’s innovation, the struggles that successful Chinese companies face when taking their brands abroad and the nation’s robust ecommerce offerings.

Clay has written numerous books, including Little Rice: Smartphones, Xiaomi, and the Chinese Dream in addition to the aforementioned Here Comes Everybody: The Power of Organizing Without Organizations. He is also a Shanghai-based associate professor with New York University’s Arthur L. Carter Journalism Institute and the school’s Interactive Telecommunications Program.

Related: NYTimes video explaining WeChat. (The future is here, it's just not evenly distributed.)

The ACME Fortune Cookie Factory


See also Isabel and the Dwarf King.
When we eat at a Chinese restaurant we usually get fortune cookies. Each cookie comes with its own mysterious message. Dad says that the messages are all written by people working at the ACME Fortune Cookie Factory. He says that he was once a fortune writer there. His masterpiece was a two-part message. The first message said WHEN YOU ARE HUNGRY EVERYTHING IS DELICIOUS. The second message said IF YOU ARE NOT HUNGRY, DON'T EAT. Millions of kids have pondered these messages. Dad says there is a life secret in these messages that most people miss -- including mom.

Dad just wrote the messages. Other workers had to make the cookies. The best worker was a little alien robot -- no one knew where he came from. Dad felt sorry for the robot, and thought he was destined for better things. Dad helped him send out the message HELP! I AM A PRISONER AT THE ACME FORTUNE COOKIE FACTORY. Dad says he doesn't know what happened to the robot.

Friday, August 05, 2016

Off the Grid in British Columbia



Who wouldn't trade their stressful modern lifestyle for an off grid homestead in British Columbia? Lovely family, beautiful locale.

Solar + Li batteries + old school technologies allow sustainable living without discomfort.

Wednesday, August 03, 2016

Machine Learning for Personalized Medicine: Heritability-based models for prediction of complex traits (David Balding)

Highly recommended talk by David Balding on modern approaches to heritability, relatedness, etc. in statistical genetics. (I listened at 1.5x normal speed, which worked for me.)



MLPM (Machine Learning for Personalized Medicine) Summer School 2015
Monday 21st of September

Heritability-based models for prediction of complex traits
by David Balding

Complex trait genetics has been revolutionised over the past 5 years by developments related to the concept of heritability. Heritability is the fraction of phenotypic variation that can be attributed to genetic mechanisms (mostly we focus on narrow-sense heritability, which considers only additive genetic effects). Since we cannot identify and measure the causal genetic mechanisms, a traditional approach has been to use pedigree relatedness as a proxy for the sharing of causal alleles between individuals. Pedigree relatedness even came to be seen as central to the concept of heritability, which perhaps explains why it was not until 2010 that it became widely appreciated that genome-wide genetic markers (SNPs) offered at least a "noisy" way to directly measure causal alleles, and hence a new approach to assessing heritability. This approach is "noisy" because SNPs generally only tag causal variants imperfectly, depending on SNP density and linkage disequilibrium, and many SNPs may tag little or no causal variation. So genome-wide SNP-based heritability estimates are difficult to interpret, but they can provide a lower bound which was enough to show that SNPs usually tag much more causal variation than can be attributed to genome-wide significant SNPs. Another big step forward has been that heritability can be attributed to different genes, genomic regions or functional classes, and for many phenotypes it is found to be widely dispersed across the genome, with relatively little concentration in coding regions. Further, heritability has become a unit of common currency for gene-based tests and meta-analysis. I will review the ideas and the underlying mathematical models, and present some recent results.
Some comments:

1. He notes that after a few hundred years, it's highly likely that a given descendant carries no actual DNA from a specific ancestor (e.g., most descendants of Shakespeare alive today have none of his DNA).

2. @18min or so: a request to Chris Chang to add a modified definition of SNP relatedness to PLINK (i.e., new flag), with a different weighting for the heterozygous (1,1) case  ;-)

3. @29min or so: finally, a discussion of systematic errors in GCTA due to LD characteristics of causal variants. As I said here:
I've always felt that the real weakness of GCTA is the assumption of random effects. A consequence of this assumption is that if the true causal variants are atypical (e.g., in terms of linkage disequilibrium) among common SNPs, the results could be biased. It is impossible to evaluate this uncertainty at the moment because we do not yet know the (full) genetic architectures of any complex traits.
See also Heritability Estimates from Summary Statistics, No Genomic Dark Matter, and HaploSNPs and missing heritability.

4. @35min: again T1D stands out in terms of genetic architecture

5. @47min: predictive correlations of almost 0.6 for T1D

Slides for this talk. Slides for another Balding lecture: Introduction to Genomic Prediction.


Tuesday, August 02, 2016

Trump: Give Peace a Chance

Thanks to a commenter for pointing me to the article below.

See also Trump, Putin, Stephen Cohen, Brawndo, and Electrolytes, Bear Baiting is Dangerous, and Obama: "Don't do stupid sh*t".
Is Trump the Peace Candidate? (Pat Buchanan)

With Democrats howling that Vladimir Putin hacked into and leaked those 19,000 DNC emails to help Trump, the Donald had a brainstorm: Maybe the Russians can retrieve Hillary Clinton’s lost emails.

Not funny, and close to “treasonous,” came the shocked cry.

Trump then told The New York Times that a Russian incursion into Estonia need not trigger a U.S. military response.

Even more shocking. By suggesting the U.S. might not honor its NATO commitment, under Article 5, to fight Russia for Estonia, our foreign policy elites declaimed, Trump has undermined the security architecture that has kept the peace for 65 years.

More interesting, however, was the reaction of Middle America. Or, to be more exact, the nonreaction. Americans seem neither shocked nor horrified. What does this suggest?

Behind the war guarantees America has issued to scores of nations in Europe, the Mideast and Asia since 1949, the bedrock of public support that existed during the Cold War has crumbled.

We got a hint of this in 2013. Barack Obama, claiming his “red line” against any use of poison gas in Syria had been crossed, found he had no public backing for air and missile strikes on the Assad regime.

The country rose up as one and told him to forget it. He did.

We have been at war since 2001. And as one looks on the ruins of Afghanistan, Iraq, Syria, Libya and Yemen, and adds up the thousands dead and wounded and trillions sunk and lost, can anyone say our War Party has served us well?

On bringing Estonia into NATO, no Cold War president would have dreamed of issuing so insane a war guarantee.

Eisenhower refused to intervene to save the Hungarian rebels. JFK refused to halt the building of the Berlin Wall. LBJ did nothing to impede the Warsaw Pact’s crushing of the Prague Spring. Reagan never considered moving militarily to halt the smashing of Solidarity.

Were all these presidents cringing isolationists?

Rather, they were realists who recognized that, though we prayed the captive nations would one day be free, we were not going to risk a world war, or a nuclear war, to achieve it. Period.

In 1991, President Bush told Ukrainians that any declaration of independence from Moscow would be an act of “suicidal nationalism.”

Today, Beltway hawks want to bring Ukraine into NATO. This would mean that America would go to war with Russia, if necessary, to preserve an independence Bush I regarded as “suicidal.”

Have we lost our minds? ...

NATO Article 5 (armed force response is optional, not required):
Article 5
The Parties agree that an armed attack against one or more of them in Europe or North America shall be considered an attack against them all and consequently they agree that, if such an armed attack occurs, each of them, in exercise of the right of individual or collective self-defence recognised by Article 51 of the Charter of the United Nations, will assist the Party or Parties so attacked by taking forthwith, individually and in concert with the other Parties, such action as it deems necessary, including the use of armed force, to restore and maintain the security of the North Atlantic area.

Monday, August 01, 2016

Trinity College Dublin iGEMS Interview



My interview with Thomas O'Reilly of Trinity College Dublin, covering topics such as genomics, CRISPR, genetic engineering, computational genomics, technology startups.

Sunday, July 31, 2016

Trump, Putin, Stephen Cohen, Brawndo, and Electrolytes




Every now and then something jars me into thinking that Idiocracy has already arrived, a bit ahead of schedule. The CNN guy on the left is obviously from the "Brawndo's got electrolytes" school of reasoning that somehow passes for journalism these days. Stephen Cohen, a distinguished emeritus professor of Russian History, is a holdover from the previous era (sadly missed, at least by me) when logic and facts actually mattered.




See also Obama: "Don't do stupid sh*t" and Bear Baiting is Dangerous.

Saturday, July 30, 2016

Perestroika and the discovery of price signals


I read The Oligarchs: Wealth And Power In The New Russia many years ago. A passage which I found fascinating, and still remember today, describes the explorations of reformist Soviet economists toward market economics and price signals. Imagine groping dimly most of your adult life for subtle but monumental concepts that lie far down a forbidden path of reasoning.

Some leftists in the West are still groping for (or perhaps not even seeking) these ideas. Just as the Soviet economists failed to appreciate for most of their lives the monstrous nature of state control of the economy, many on the left take for granted the miraculous fruits of the market economy.
[Chapter 4: Anatoly Chubais] ... As perestroika dawned with the arrival of Gorbachev in 1985, the topics at the Leningrad seminars grew more ambitious. The participants began to broach an altogether bold idea: introducing some aspects of the market to Soviet socialism. For a long time, they intensely debated whether the economy could be saved by such reform concepts as self-financing or by decentralization, which meant allowing factory directors to make more of their own decisions. Later, as the years went on, they concluded that the existing machine was probably doomed and would have to be massively restructured. Still later, they spent many days contemplating the prospect of a “transition” to some new kind of a system. Even the notion of a “transition” was a thrilling idea.

... They had ample access to more radical texts in samizdat, the dog-eared, self-typed, or mimeographed manuscripts that were officially prohibited but widely distributed from hand to hand. ...

Then came a sudden bolt of inspiration. They were profoundly inspired by a two-volume, 630-page book published in 1980 by a Hungarian economics professor, János Kornai. The Economics of Shortage, more than any other text, offered an insight into the failings of Soviet socialism. Hungary had been at the forefront of more market-oriented economic reform in the Eastern Bloc since 1968, and Kornai’s groundbreaking work was almost entirely based on his observations about Hungary. But for the young scholars around Chubais, the work opened a window as no other Soviet or Western study had done on why the economy of shortage existed and how it functioned. Kornai examined the behavior of buyers, sellers, and producers in an absence of free prices, as well as the relationship between firms and the state under socialism and central planning. [ See János Kornai’s Contributions to Economic Analysis. ]

The book first arrived in Leningrad as smuggled photocopies and instantly “became a Bible,” Vasiliev recalled. “We had some ideas initially, but the book was kind of a catharsis. It pushed our thinking forward. You met a person and you said, ‘Have you read Kornai? Yes?’ And then it was a starting point for discussion. ...

But Kornai alone did not lead the Chubais team out of socialism; he just helped them see it much more clearly. The other great inspiration of those years came from the Austrian economist Friedrich von Hayek, one of the most trenchant early critics of socialism, who was especially acute in his searing denunciation of central planning. Although Hayek’s best-known work was The Road to Serfdom, a 1944 treatise about the dangers to individual liberty of socialism and central planning, Chubais took to heart a lesser-known economics text.11 It was an article that Hayek had published in 1945, “The Use of Knowledge in Society.”12 The article articulated clearly what the Leningrad scholars had been groping toward since the debate at the collective farm: that free prices were the single most powerful “indicator” to measure all the millions of decisions in a large, complex economy. ...

Hayek declared that the price system was a “marvel” which could free people from the “conscious control” of the central planners. At the time Chubais read this essay in Leningrad, the Soviet Union was the world’s largest example of “conscious control,” with rigid, fixed state prices set throughout the economy. Hayek, who won the 1974 Nobel Prize in economics for his work, had taken a battering ram to the underpinnings of Soviet socialism. Amazingly, his wisdom was smuggled past the KGB on those dog-eared photocopies, and it landed in the hands of an eager young generation of knowledge-hungry Leningrad academics.

Many years later, Chubais recalled the thrill of reading Hayek and instantly gave his own example of how Hayek’s theory worked in practice in the United States. “One person is selling hamburgers somewhere in New York,” he told me, “while another person is grazing cows somewhere in Arkansas to produce meat that will be used to make those hamburgers. But in order for that person in Arkansas to graze cows, there needs to be a price for meat, which tells him that he should graze cows.” ...

... “We started trying to think about real things, instead of all that bullshit we were engaged in during our formal jobs,” Glazkov said. The Gaidar-Chubais group produced a 120-page report, adapting some of the Hungarian and Yugoslav reforms to the Soviet system. They called for abandoning planning dictates and permitting some free market mechanisms. When Gaidar’s boss came back one day, he brought bad news: the plan had been rejected. “Which meant we were to give up our fruitless daydreaming” and come up with something “on a more mundane level,” Gaidar recalled. But when Gaidar went home that day and turned on the television, he heard Gorbachev deliver a speech using some of the same terms they had put in the rejected report. It was a strange time ...
My samizdat.

Friday, July 29, 2016

Michael Moore: Trump Will Win


Michael Moore received an honorary degree from Michigan State University in December 2014. Said I to the packed Breslin Center: "President Simon, it is my honor to present Michael Moore for the degree Doctor of Humanities." :-)
michaelmoore.com: ... I am sorry to be the bearer of bad news, but I gave it to you straight last summer when I told you that Donald Trump would be the Republican nominee for president. And now I have even more awful, depressing news for you: Donald J. Trump is going to win in November. This wretched, ignorant, dangerous part-time clown and full time sociopath is going to be our next president. President Trump. Go ahead and say the words, ‘cause you’ll be saying them for the next four years: “PRESIDENT TRUMP.”

Never in my life have I wanted to be proven wrong more than I do right now.

I can see what you’re doing right now. You’re shaking your head wildly – “No, Mike, this won’t happen!” Unfortunately, you are living in a bubble that comes with an adjoining echo chamber where you and your friends are convinced the American people are not going to elect an idiot for president. You alternate between being appalled at him and laughing at him because of his latest crazy comment or his embarrassingly narcissistic stance on everything because everything is about him. And then you listen to Hillary and you behold our very first female president, someone the world respects, someone who is whip-smart and cares about kids, who will continue the Obama legacy because that is what the American people clearly want! Yes! Four more years of this!

You need to exit that bubble right now. You need to stop living in denial and face the truth which you know deep down is very, very real. Trying to soothe yourself with the facts – “77% of the electorate are women, people of color, young adults under 35 and Trump cant win a majority of any of them!” – or logic – “people aren’t going to vote for a buffoon or against their own best interests!” – is your brain’s way of trying to protect you from trauma. Like when you hear a loud noise on the street and you think, “oh, a tire just blew out,” or, “wow, who’s playing with firecrackers?” because you don’t want to think you just heard someone being shot with a gun. It’s the same reason why all the initial news and eyewitness reports on 9/11 said “a small plane accidentally flew into the World Trade Center.” We want to – we need to – hope for the best because, frankly, life is already a shit show and it’s hard enough struggling to get by from paycheck to paycheck. We can’t handle much more bad news. So our mental state goes to default when something scary is actually, truly happening. The first people plowed down by the truck in Nice spent their final moments on earth waving at the driver whom they thought had simply lost control of his truck, trying to tell him that he jumped the curb: “Watch out!,” they shouted. “There are people on the sidewalk!”

Well, folks, this isn’t an accident. It is happening. And if you believe Hillary Clinton is going to beat Trump with facts and smarts and logic, then you obviously missed the past year of 56 primaries and caucuses where 16 Republican candidates tried that and every kitchen sink they could throw at Trump and nothing could stop his juggernaut. As of today, as things stand now, I believe this is going to happen – and in order to deal with it, I need you first to acknowledge it ...

And therein lies the problem for November – who is going to have the most motivated, most inspired voters show up to vote? You know the answer to this question. Who’s the candidate with the most rabid supporters? Whose crazed fans are going to be up at 5 AM on Election Day, kicking ass all day long, all the way until the last polling place has closed, making sure every Tom, Dick and Harry (and Bob and Joe and Billy Bob and Billy Joe and Billy Bob Joe) has cast his ballot? That’s right. That’s the high level of danger we’re in. And don’t fool yourself — no amount of compelling Hillary TV ads, or outfacting him in the debates or Libertarians siphoning votes away from Trump is going to stop his mojo. 
Here are the 5 reasons Trump is going to win:

1. Midwest Math, or Welcome to Our Rust Belt Brexit. I believe Trump is going to focus much of his attention on the four blue states in the rustbelt of the upper Great Lakes – Michigan, Ohio, Pennsylvania and Wisconsin. Four traditionally Democratic states – but each of them have elected a Republican governor since 2010 (only Pennsylvania has now finally elected a Democrat). In the Michigan primary in March, more Michiganders came out to vote for the Republicans (1.32 million) that the Democrats (1.19 million). Trump is ahead of Hillary in the latest polls in Pennsylvania and tied with her in Ohio. Tied? How can the race be this close after everything Trump has said and done? Well maybe it’s because he’s said (correctly) that the Clintons’ support of NAFTA helped to destroy the industrial states of the Upper Midwest. Trump is going to hammer Clinton on this and her support of TPP and other trade policies that have royally screwed the people of these four states. When Trump stood in the shadow of a Ford Motor factory during the Michigan primary, he threatened the corporation that if they did indeed go ahead with their planned closure of that factory and move it to Mexico, he would slap a 35% tariff on any Mexican-built cars shipped back to the United States. It was sweet, sweet music to the ears of the working class of Michigan, and when he tossed in his threat to Apple that he would force them to stop making their iPhones in China and build them here in America, well, hearts swooned and Trump walked away with a big victory that should have gone to the governor next-door, John Kasich.

From Green Bay to Pittsburgh, this, my friends, is the middle of England – broken, depressed, struggling, the smokestacks strewn across the countryside with the carcass of what we use to call the Middle Class. Angry, embittered working (and nonworking) people who were lied to by the trickle-down of Reagan and abandoned by Democrats who still try to talk a good line but are really just looking forward to rub one out with a lobbyist from Goldman Sachs who’ll write them nice big check before leaving the room. What happened in the UK with Brexit is going to happen here. ...

2. The Last Stand of the Angry White Man ... a small peek into the mind of the Endangered White Male. There is a sense that the power has slipped out of their hands, that their way of doing things is no longer how things are done. This monster, the “Feminazi,”the thing that as Trump says, “bleeds through her eyes or wherever she bleeds,” has conquered us — and now, after having had to endure eight years of a black man telling us what to do, we’re supposed to just sit back and take eight years of a woman bossing us around? After that it’ll be eight years of the gays in the White House! Then the transgenders! You can see where this is going. By then animals will have been granted human rights and a fuckin’ hamster is going to be running the country. This has to stop!

3. The Hillary Problem ... her vote for the Iraq War made me promise her that I would never vote for her again. ... Let’s face it: Our biggest problem here isn’t Trump – it’s Hillary. She is hugely unpopular — nearly 70% of all voters think she is untrustworthy and dishonest. She represents the old way of politics, not really believing in anything other than what can get you elected. That’s why she fights against gays getting married one moment, and the next she’s officiating a gay marriage. Young women are among her biggest detractors, which has to hurt ...

4. The Depressed Sanders Vote. ... The fire alarm that should be going off is that while the average Bernie backer will drag him/herself to the polls that day to somewhat reluctantly vote for Hillary, it will be what’s called a “depressed vote” – meaning the voter doesn’t bring five people to vote with her. He doesn’t volunteer 10 hours in the month leading up to the election. She never talks in an excited voice when asked why she’s voting for Hillary. A depressed voter. Because, when you’re young, you have zero tolerance for phonies and BS. Returning to the Clinton/Bush era for them is like suddenly having to pay for music, or using MySpace or carrying around one of those big-ass portable phones. They’re not going to vote for Trump; some will vote third party, but many will just stay home.

5. The Jesse Ventura Effect. ... the voting booth. It’s one of the few places left in society where there are no security cameras, no listening devices, no spouses, no kids, no boss, no cops, there’s not even a friggin’ time limit. You can take as long as you need in there and no one can make you do anything. ... There are no rules. And because of that, and the anger that so many have toward a broken political system, millions are going to vote for Trump not because they agree with him, not because they like his bigotry or ego, but just because they can. ...

Thursday, July 28, 2016

Bear baiting is dangerous



What do we have to gain by placing interceptor missiles in Romania? Putin's concerns are legitimate, and security through Mutually Assured Destruction has always been an unstable equilibrium. Watch the video closely.
RT.com: ... “At the moment the interceptor missiles installed have a range of 500 kilometers, soon this will go up to 1000 kilometers, and worse than that, they can be rearmed with 2400km-range offensive missiles even today, and it can be done by simply switching the software, so that even the Romanians themselves won’t know,” said Putin, who is in Greece for a two-day tour.

“We have the capability to respond. The whole world saw what our medium-range sea-based missiles are capable of [in Syria]. But we violate no agreements. And our ground-based Iskander missiles have also proven themselves as superb,” continued Putin.

Russia’s political and military leadership has repeatedly spoken out against the missile defense shield since it was proposed during the George W. Bush administration, and Putin reiterated that Moscow does not believe the European part of it is targeted against a potential threat from Iran.

“NATO fend us off with vague statements that this is no threat to Russia… That the whole project began as a preventive measure against Iran’s nuclear program. Where is that program now? It doesn’t exist,” said Putin, referring to the nuclear treaty that was concluded between the world’s major powers and Tehran last year. “We have been saying since the early 2000s that we will have to react somehow to your moves to undermine international security. No one is listening to us.”
Link to full interview and better translation.
They have built this system and are now delivering missiles there. You probably know that the launch systems of the Tomahawk sea-launched intermediate-range missiles will be used to launch anti-missiles with an effective range of 500 kilometres. However, technology does not stand still, and we know more or less precisely when the Americans will create a new missile that will have a range of 1,000 kilometres or more. From that time on, they will be a threat to our nuclear arsenals.

We know what will happen and in which year, and they know we know it. They are just throwing dust in our eyes, as the saying goes, and you in turn are throwing dust in the eyes of your people. What bothers me is that people are not aware of the danger. We fail to understand that we are dragging the world into a completely new dimension. This is what this is all about. They are pretending as if nothing is going on. I do not even know how to put my message across.

We are being told that this is part of a defensive, not offensive, capability, that these systems are intended to ensure defence against aggression. This is not true. This is not the way things are. A strategic missile defence system is part of an offensive strategic capability, and is tightly linked to offensive missile strike systems. Some high-precision weapons are used to carry out a pre-emptive strike, while others serve as a shield against a retaliatory strike, and still others carry out nuclear strikes. All these objectives are related, and go hand in hand with the use of high-precision conventional weapons.

All right, even if we put aside the interceptor missiles that will be developed in the future, increasingly threatening Russia, but the launch tubes where these missiles are stored, as I said, are the same that are used on navy ships to carry Tomahawk missiles. You can replace interceptor missiles with Tomahawks in a matter of hours and these tubes will no longer be used to intercept missiles. How do we know what is inside them? All they need is to change the software. This can be done seamlessly; even the Romanians would not know what is going on, since they cannot access these facilities, right? No one will know, neither the Romanians, nor the Poles. I know how this is done. In my opinion, this is a major threat.

When we discussed this with our US partners, they had the idea of creating nonnuclear ballistic missiles. We said, “Listen, do you understand what this would be? Imagine that you fire a submarine-launch or land-based missile. A ballistic missile is launched. How do we know whether it is carrying a nuclear warhead or not? Do you understand the kind of threat this would create?” As far as we know, this programme is currently suspended. They have stopped it for now. However, they are still working on it.

I do not know where this will take us. However, Russia will definitely have to retaliate. I know already that we will be accused of acting aggressively, even though all we do is respond. It is clear that we will have to ensure security, and not just in Russia, since ensuring the strategic balance of power globally is a matter of great importance for us.

Tuesday, July 26, 2016

Genomics of complex traits and evolutionary selection pressure on DNA regions linked to cognitive ability

Two recent papers relevant to the genetics of complex traits. The second paper is specifically about the genetic architecture of cognition. Thanks to blog readers for pointing them out to me.

See also The tipping point.
Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

DOI: 10.1098/rspb.2016.0569
Proceedings of the Royal Society 27 July 2016 Volume 283, issue 1835

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

http://dx.doi.org/10.1101/063636

Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

Monday, July 25, 2016

The Mendel of Cancer Genetics


See also earlier post Where Men are Men and Giants Walk the Earth.
NYTimes: Dr. Alfred G. Knudson, the ‘Mendel of Cancer Genetics,’ Dies at 93

Dr. Alfred G. Knudson, who deduced how certain cancers strike a family generation after generation, died on Sunday at his home in Philadelphia. He was 93.

... “Funny as it may sound, heritable cancer was hardly discussed in the 1960s and 1970s,” Dr. Albert de la Chapelle, a professor in the human genetics program at Ohio State University, said in an email.

Dr. Knudson, trained as a pediatrician, tackled the issue by looking at retinoblastoma, a cancer of the eye that strikes children, even newborns. Childhood cancers would be easier to understand, he reasoned, because there would be fewer confounding factors, like the random mutations that accumulate over a lifetime.

“It had been known for a long time that there were inherited forms of retinoblastoma, that it would run in families,” said Dr. Jonathan Chernoff, the chief scientific officer at Fox Chase. “And then there were, on the other hand, sporadic cases that didn’t run in families. Some child would randomly get retinoblastoma.”

Dr. Knudson analyzed the records of retinoblastoma patients and found that the inherited form struck children at a younger age and often in both eyes, while the sporadic cases usually involved older children and just one eye.

That led him to his “two-hit” hypothesis, and his insight that cancer sometimes results not from a particular cause, but rather from the disabling of something known today as the tumor suppressor gene.

... Dr. Chernoff said Dr. Knudson was in some ways “the Mendel of cancer genetics,” referring to Gregor Mendel, the 19th-century monk who demonstrated, through the crossbreeding of pea plants, how traits are passed from one generation to the next.

“He provided the conceptual framework for how we think about cancer now,” Dr. Chernoff said.

Dr. Knudson published his hypothesis in 1971. “Knudson’s hypothesis was conceived before we had a clue about the underlying molecular genetic events,” Dr. de la Chapelle said. “I believe Knudson’s work stimulated retinoblastoma researchers so strongly that this led to an early breakthrough.”

Dr. Knudson’s theory was proved in 1986, when researchers figured out the gene and the mutations that led to the disease.

... Alfred George Knudson Jr. was born on Aug. 9, 1922, in Los Angeles. He went to the California Institute of Technology thinking he would major in physics.

“I had never had any biology in high school,” he recalled in a 2013 interview. “Then, after two years of physics at Caltech, I thought: ‘Oh, they know everything in physics. Why do I want to go into physics?’”

The quantitative aspects of genetics appealed to him, he said: “It has some of the features I admire about physics, so I’ll study that.”

He finished his bachelor of science degree at Caltech in 1944 and went on to receive a medical degree from Columbia in 1947. He returned to Caltech to earn a doctorate in biochemistry and genetics in 1956. He served in the Navy during World War II and the Army during the Korean War.

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