Monday, December 30, 2013

The Gene Factory (New Yorker)


A Chinese firm’s bid to crack hunger, illness, evolution—and the genetics of human intelligence.


A well-balanced article about BGI in the New Yorker.

I am misquoted about our current ability to predict height from genomic information, despite an hour on the phone with the Harvard-educated fact checker. There is also some confusion in that paragraph concerning the correlation between height and IQ and its relevance to the broader discussion  :-(

Chris Chang has the wise, last words in the article :-)  Click for larger version.

Research rankings

Some notes for my own use on research rankings by discipline for Michigan State University. The ranges are 95% confidence intervals using the R-rank (including, among other things, publications, citations, grants and awards) from the 2010 NRC evaluation (see, e.g., here). Rank ordered by, e.g., central value of R range, most of the departments below come out in the top 20-30 in the US. More data: S rankings in various fields.

Physics                                     17-41
Chemistry                                 21-59
Computer Science                    12-32
Math                                         11-43
EE/CE                                      47-87
Biochem/MoBio                      54-96
Neuroscience                            72-89
Plant Biology                            6-32

In the NSF HERD (total R&D expenditures) data MSU is ranked 36th in the US, with 2012 expenditures just over $500 million. If research hospital numbers are excluded (MSU has historically had a teaching medical school, although this is changing), the MSU rank would be quite a bit higher.

Tuesday, December 24, 2013

Peace on Earth, Good Will to Men 2013

For years, when asked what I wanted for Christmas, I've been replying: peace on earth, good will toward men :-)

No one ever seems to recognize that this comes from the bible, Luke 2.14 to be precise!

Linus said it best in A Charlie Brown Christmas:
And there were in the same country shepherds abiding in the field, keeping watch over their flock by night.

And, lo, the angel of the Lord came upon them, and the glory of the Lord shone round about them: and they were sore afraid.

And the angel said unto them, Fear not: for, behold, I bring you good tidings of great joy, which shall be to all people.

For unto you is born this day in the city of David a Saviour, which is Christ the Lord.

And this shall be a sign unto you; Ye shall find the babe wrapped in swaddling clothes, lying in a manger.

And suddenly there was with the angel a multitude of the heavenly host praising God, and saying,

Glory to God in the highest, and on earth peace, good will toward men.

Merry Christmas!

Here's a longer excerpt from A Charlie Brown Christmas.

Back in the day

Two old photos I discovered at my mom's house. These would be from 1986 (the graduation photo) and probably a year or two after that for the other one (taken in our garage in Iowa during Xmas break, check out the penny loafers!).

Here's an old Wham! video from the same era :-) Eighties forever!

Saturday, December 21, 2013

The dawn of genetic engineering?

Some CRISPR links. This technology is for real. See earlier post CRISPR. Watch realtime action hereGeCKO knockout in human cells.

Zhang and Church raise $43M for new venture Editas.

Application to Cystic Fibrosis in human stem cells , Cataracts in mouse.
The Scientist: It was less than a year ago that scientists first applied CRISPR, a genome-editing technique, to human cells. In short order, the technique has taken off like wildfire. And now, two papers appearing in Cell Stem Cell today (December 5) show that CRISPR can be used to rewrite genetic defects to effectively cure diseases in mice and human stem cells.

“What’s significant about this is it’s taking CRISPR to that next step of what it can be used for, and in this case, it’s correcting mutations that cause disease,” said Charles Gersbach, a genomics researcher at Duke University, who was not involved in either study.

CRISPR stands for clustered regularly interspaced short palindromic repeats. These RNA sequences serve an immune function in archaea and bacteria, but in the last year or so, scientists have seized upon them to rewrite genes. The RNA sequence serves as a guide to target a DNA sequence in, say, a zygote or a stem cell. The guide sequence leads an enzyme, Cas9, to the DNA of interest. Cas9 can cut the double strand, nick it, or even knock down gene expression. After Cas9 injures the DNA, repair systems fix the sequence—or new sequences can be inserted.

In one of the new papers, a team from China used CRISPR/Cas9 to replace a single base pair mutation that causes cataracts in mice. The researchers, led by Jinsong Li at the Shanghai Institute for Biological Sciences, designed a guide RNA that led Cas9 to the mutant allele where it induced a cleavage of the DNA. Then using either the other wild-type allele or oligos given to the zygotes repair mechanisms corrected the sequence of the broken allele.

Li said that about 33 percent of the mutant zygotes that were injected with CRISPR/Cas9 grew up to be cataract-free mice. In an e-mail to The Scientist, Li said the efficiency of the technique was low, “and, for clinical purpose, the efficiency should reach 100 percent.”

Still, this was the first time CRISPR had been used to cure a disease in a whole animal, an advance that Jennifer Doudna, a leader in CRISPR technology at the University of California, Berkeley, said was encouraging. Both studies “show the potential for using the technology to correct disease-causing mutations, and that’s what very exciting here,” she said.

Hans Clevers, a stem cell researcher at the Hubrecht Institute in Utrecht, The Netherlands, led the other study, which used CRISPR/Cas9 to correct a defect associated with cystic fibrosis in human stem cells. The team’s target was the gene for an ion channel, cystic fibrosis transmembrane conductor receptor (CFTR). A deletion in CFTR causes the protein to misfold in cystic fibrosis patients.

Using cultured intestinal stem cells developed from cell samples from two children with cystic fibrosis, Clevers’s team was able to correct the defect using CRISPR along with a donor plasmid containing the reparative sequence to be inserted. The researchers then grew the cells into intestinal “organoids,” or miniature guts, and showed that they functioned normally. In this case, about half of clonal organoids underwent the proper genetic correction, Clevers said.

For both studies, the researchers did not have to make significant modifications to existing CRISPR protocols. Clevers said in an e-mail to The Scientist that, compared with other gene editing techniques, CRISPR was straightforward. “We tried TALENs [transcription activator-like effector nucleases] and Zinc finger approaches. CRISPR is exquisitely fast and simple,” Clevers said. Li agreed. “I think CRISPR/Cas9 system may be the easiest strategy to cure genetic disease than any other available gene-editing techniques,” he said.

One limitation of CRISPR is that the approach can create off-target effects—alterations to sites other than the target DNA. In both studies, off-target effects were relatively rare, said Gersbach. “While reducing off-target effects is a priority, it’s unrealistic to think you’d be able to get rid of all off-target effects,” he told The Scientist.

While the approach is far from ready for prime time, the results of both these studies show promise for future clinical potential. “I think each time an advance like this is made, people are more sure that this is a technique that is likely to be useful in treating humans,” said Doudna.

Friday, December 20, 2013

One in a thousand

Good evening. The organizers have seen fit to place me on the schedule between you and dinner. So I will be mercifully brief.

As Terry mentioned, we had the awesome task of reviewing 150 promotion files last year. The word "awesome" can mean many things. Here it means humbling. It was humbling to review the impressive files of the full professor candidates. Our university is fortunate to have such tremendously accomplished faculty.

Terry, the Provost, and I upheld the highest standards in full professor promotion cases. Each and every person being honored here tonight has made important contributions to scholarship and learning, and is an invaluable member of our university community.

A final remark before we eat our rubber chickens. It is often said that we are entering or have entered the age of the knowledge economy -- that a person's contributions will be from their knowledge, intelligence, and creativity. But when an attorney prepares a case it is for her client. When a Google engineer develops a new algorithm, it is for Google -- for money. Fewer than one in a thousand individuals in our society have the privilege, the freedom, to pursue their own ideas and creations. The vast majority of such people are at research universities. A smaller number are at think tanks or national labs, but most are professors like yourselves. It is you who will make the future better than the past; who will bring new wonders into existence. Your work may be largely invisible to our fellow citizens, but the future owes its greatness to you. My sincere congratulations.

Neanderthals dumb?

This figure is from the Supplement (p.62) of a recent Nature paper describing a high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression; see earlier post Structural genomic variants (CNVs) affect cognition.

From the Supplement (p.62):
Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.

My recollection from the earlier (less precise) neanderthal sequences is that the number of bp differences between them and us is few per thousand. Whereas, for modern humans it's 1 per thousand with an additional +/-15% variation due to ethnicity. So, I think it's fair to say that they are qualitatively much more different from us than we (moderns) are from each other. See also The genetics of humanness.

My colleague James Lee (I note he is too modest to list his Harvard Law degree on his faculty page!) describes the current era in genomics as an "age of wonder" :-)  We can anticipate tremendous discoveries in the next decade.

Wednesday, December 18, 2013

Structural genomic variants (CNVs) affect cognition

CNVs (structural genomic variants) associated with increased autism and schizo risk are found to depress cognitive function in carriers who do not present for either condition. There are also effects on physical brain structure.

This is the future of neuroscience: read out the genome and look for the direct effect on phenotype. Assuming the results hold up, we can conclude that these mutations cause abnormal cognitive function in humans. We are just at the beginning of this line of research: mutations of smaller effect size will require larger samples to detect, but they almost certainly exist.

Note this is deCODE and Kari Stefansson -- they have access to all health records and genotypes in Iceland. See also deCODE, de novo mutations, and autism risk.
CNVs conferring risk of autism or schizophrenia affect cognition in controls (Nature)

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
This figure shows impairment in population SDs for different groups. V IQ and P IQ are Verbal and Performance IQ (Wechsler), IIUC.

From the Supplement -- check out the p values ;-)

My guess is that most intelligence alleles have negative effect. That is, the majority of genetic variation in cognitive ability is determined by the number and type of somewhat deleterious mutations we all carry around. (There are probably also minor alleles of positive effect, but fewer of them.) Note the CNVs in this article, while having a significantly (1 SD) negative effect on IQ, do not prevent reproduction (fecundity is reduced, but not to zero), so clearly mutations of large effect can linger for some generations. Mutations of smaller effect might even be neutral due to pleiotropy, etc.

Her: Singularity as romantic comedy

Can't quite decide whether this is a dystopian or utopian future  :-)
New Yorker ...Spike Jonze’s movie, which was shot in Los Angeles and Shanghai, is set in a near but dateless future, where the rough edges of existence have been rubbed away. The colors of clothes and furnishings, though citrus-bright, are diluted by the pastel softness of the lighting, so that nothing hurts the eye. People ride in smoothly humming trains, not belching cars. And Theodore’s cell phone reminds you of those slender vintage cases for cigarettes and visiting cards; if the ghost of Steve Jobs is watching, he will glow a covetous green.

This little flat box, plus an earpiece that Theodore plugs in whenever he wakes up or can’t sleep, is his portal. It links him to OS1, “the first artificially intelligent operating system,” which is newly installed on his computer. More than that, “it’s a consciousness,” with a voice of your choice, and a rapidly evolving personality, which grows not like a baby, or a library, but like an unstoppable alien spore. Theodore’s version is called Samantha, and practically her first request is: “You mind if I look through your hard drive?” She tidies his e-mails, reads a book in two-hundredths of a second, fixes him up on a date, and, when that goes badly, has sex with him—aural sex, so to speak, but Theodore will take what he can get. No surprise, really, given that the role of Samantha is spoken by Scarlett Johansson.

... And it is romantic: Theodore and Samantha click together as twin souls, not caring that one soul is no more than a digital swarm. Sad, kooky, and daunting in equal measure, “Her” is the right film at the right time. It brings to full bloom what was only hinted at in the polite exchanges between the astronaut and hal, in “2001: A Space Odyssey,” and, toward the end, as Samantha joins forces with like minds in cyberspace, it offers a seductive, nonviolent answer to Skynet, the system in the “Terminator” films that attacked its mortal masters. We are easy prey, not least when we fall in love.

Sunday, December 15, 2013

Yuri Slezkine: The Jewish Century

Yuri Slezkine of UC Berkeley, author of The Jewish Century (reviewed in The Nation).

@7 min "I was unprincipled enough to put down Russian in all my official paperwork because, obviously, it made it much easier to get into college." [ Slezkine is half Jewish; his father is Russian. See They take students like you there and I'm not Asian. ]

@29:30 The evolution of anti-semitism in the Soviet Union. From an overrepresentation of Jews in the early Soviet leadership, to (post-WWII and -Stalin) an era of quotas and overt discrimination, and an increasing identification of the Soviet state with Russian nationality.

From the introduction to The Jewish Century:
The Modern Age is the Jewish Age, and the twentieth century, in particular, is the Jewish Century. Modernization is about everyone becoming urban, mobile, literate, articulate, intellectually intricate, physically fastidious, and occupationally flexible. It is about learning how to cultivate people and symbols, not fields or herds. It is about pursuing wealth for the sake of learning, learning for the sake of wealth, and both wealth and learning for their own sake. It is about transforming peasants and princes into merchants and priests, replacing inherited privilege with acquired prestige, and dismantling social estates for the benefit of individuals, nuclear families, and book-reading tribes (nations). Modernization, in other words, is about everyone becoming Jewish.

Some peasants and princes have done better than others, but no one is better at being Jewish than the Jews themselves. In the age of capital, they are the most creative entrepreneurs; in the age of alienation, they are the most experienced exiles; and in the age of expertise, they are the most proficient professionals. Some of the oldest Jewish specialties-commerce, law, medicine, textual interpretation, and cultural mediation-have become the most fundamental (and the most Jewish) of all modern pursuits. It is by being exemplary ancients that the Jews have become model moderns. ...

Lévi-Strauss in Tokyo

Claude Lévi-Strauss has been called the father of modern (social) anthropology. He lived to be 100 years old, passing in 2009. I recommend his Tristes Tropiques, a memoir of time in the jungles of Brazil (full text in English). The lectures in the book below were delivered in Tokyo in 1986.
Anthropology Confronts the Problems of the Modern World

(p. 98-99) And who knows whether aggressive or contemplative dispositions, technical ingenuity, and so on, are not partly linked to genetic factors? None of these traits, as we apprehend them at the cultural level, can be clearly linked to a genetic foundation, but we cannot rule out a priori the distant effects of intermediate links. If such effects are real, it would be true to say that every culture selects genetic abilities that, by retroaction, influence the culture and reinforce its orientation.

Saturday, December 14, 2013

Go train jiujitsu!

Some beautiful jiujitsu from ADCC 2013.

Estima v. Galvao superfight:

I hadn't been on the mat in a long time, but over Thanksgiving I had a chance to show some things to my nephew. Almost ten years of training -- not all of it is gone yet :-)

Tuesday, December 10, 2013

Is science self-correcting?

More fun from our man Ioannidis. See earlier posts Medical science? , NIH discovers reproducibility and Bounded cognition.

A toy model of the dynamics of scientific research, with probability distributions for accuracy of experimental results, mechanisms for updating of beliefs by individual scientists, crowd behavior, bounded cognition, etc. can easily exhibit parameter regions where progress is limited (one could even find equilibria in which most beliefs held by individual scientists are false!). Obviously the complexity of the systems under study and the quality of human capital in a particular field are important determinants of the rate of progress and its character.

In physics it is said that successful new theories swallow their predecessors whole. That is, even revolutionary new theories (e.g., special relativity or quantum mechanics) reduce to their predecessors in the previously studied circumstances (e.g., low velocity, macroscopic objects). Swallowing whole is a sign of proper function -- it means the previous generation of scientists was competent: what they believed to be true was (at least approximately) true. Their models were accurate in some limit and could continue to be used when appropriate (e.g., Newtonian mechanics).

In some fields (not to name names!) we don't see this phenomenon. Rather, we see new paradigms which wholly contradict earlier strongly held beliefs that were predominant in the field* -- there was no range of circumstances in which the earlier beliefs were correct. We might even see oscillations of mutually contradictory, widely accepted paradigms over decades.

It takes a serious interest in the history of science (and some brainpower) to determine which of the two regimes above describes a particular area of research. I believe we have good examples of both types in the academy.

* This means the earlier (or later!) generation of scientists in that field was incompetent. One or more of the following must have been true: their experimental observations were shoddy, they derived overly strong beliefs from weak data, they allowed overly strong priors to determine their beliefs.

Why Science Is Not Necessarily Self-Correcting 
(DOI: 10.1177/1745691612464056)

John P. A. Ioannidis
Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, and Department of Statistics, Stanford University School of Humanities and Sciences

The ability to self-correct is considered a hallmark of science. However, self-correction does not always happen to scientific evidence by default. The trajectory of scientific credibility can fluctuate over time, both for defined scientific fields and for science at-large. History suggests that major catastrophes in scientific credibility are unfortunately possible and the argument that “it is obvious that progress is made” is weak. Careful evaluation of the current status of credibility of various scientific fields is important in order to understand any credibility deficits and how one could obtain and establish more trustworthy results. Efficient and unbiased replication mechanisms are essential for maintaining high levels of scientific credibility. Depending on the types of results obtained in the discovery and replication phases, there are different paradigms of research: optimal, self-correcting, false nonreplication, and perpetuated fallacy. In the absence of replication efforts, one is left with unconfirmed (genuine) discoveries and unchallenged fallacies. In several fields of investigation, including many areas of psychological science, perpetuated and unchallenged fallacies may comprise the majority of the circulating evidence. I catalogue a number of impediments to self-correction that have been empirically studied in psychological science. Finally, I discuss some proposed solutions to promote sound replication practices enhancing the credibility of scientific results as well as some potential disadvantages of each of them. Any deviation from the principle that seeking the truth has priority over any other goals may be seriously damaging to the self-correcting functions of science

Sunday, December 08, 2013

Corrupt practices

OK for Harvard but not for JP. Legacy and "strategic" admits still a big chunk of each entering class. Foreign Corrupt Practices Act.
NYTimes: Federal authorities have obtained confidential documents that shed new light on JPMorgan Chase’s decision to hire the children of China’s ruling elite, securing emails that show how the bank linked one prominent hire to “existing and potential business opportunities” from a Chinese government-run company.

The documents, which also include spreadsheets that list the bank’s “track record” for converting hires into business deals, offer the most detailed account yet of JPMorgan’s “Sons and Daughters” hiring program, which has been at the center of a federal bribery investigation for months. The spreadsheets and emails — recently submitted by JPMorgan to authorities — illuminate how the bank created the program to prevent questionable hiring practices but ultimately viewed it as a gateway to doing business with state-owned companies in China, which commonly issue stock with the help of Wall Street banks.

Thursday, December 05, 2013

NIH discovers reproducibility

When someone first described to me the evidence-based medicine movement, I responded (shocked): "Is that like science-based science? What were they doing before?"
Nature News: In biomedical science, at least one thing is apparently reproducible: a steady stream of studies that show the irreproducibility of many important experiments.

In a 2011 internal survey, pharmaceutical firm Bayer HealthCare of Leverkusen, Germany, was unable to validate the relevant preclinical research for almost two-thirds of 67 in-house projects. Then, in 2012, scientists at Amgen, a drug company based in Thousand Oaks, California, reported their failure to replicate 89% of the findings from 53 landmark cancer papers. And in a study published in May, more than half of the respondents to a survey at the MD Anderson Cancer Center in Houston, Texas, reported failing at least once in attempts at reproducing published data (see 'Make believe').

The growing problem is threatening the reputation of the US National Institutes of Health (NIH) based in Bethesda, Maryland, which funds many of the studies in question. Senior NIH officials are now considering adding requirements to grant applications to make experimental validations routine for certain types of science, such as the foundational work that leads to costly clinical trials. ...
A comment from a researcher quoted in the article notes
... a broader need to shift biomedical research from categorical statements and simple schematics to quantifiable hypotheses backed up by modeling and computation, open access to data (itself requiring new approaches and infrastructure) and better application of probability theory and statistics.
See also Medical science? (are most research findings false?) and Bounded cognition.

Monday, December 02, 2013

PLINK 1.90 alpha

WDIST is now PLINK 1.9 alpha. WDIST (= "weighted distance" calculator) was originally written to compute pairwise genomic distances. The mighty Chris Chang then amazingly re-implemented all of PLINK with significant improvements (see below).

PLINK 1.9 even has support for LASSO (i.e., L1 penalized optimization, a particular method for Compressed Sensing).
This is a comprehensive update to Shaun Purcell's popular PLINK command-line program, developed by Christopher Chang with support from the NIH-NIDDK's Laboratory of Biological Modeling and others. (What's new?) (Credits.)

It isn't finished yet (hence the 'alpha' designation), but it's getting there. We are working with Dr. Purcell to launch a large-scale beta test in the near future. ...

Unprecedented speed 
Thanks to heavy use of bitwise operators, sequential memory access patterns, multithreading, and higher-level algorithmic improvements, PLINK 1.9 is much, much faster than PLINK 1.07 and other popular software. Several of the most demanding jobs, including identity-by-state matrix computation, distance-based clustering, LD-based pruning, and association analysis max(T) permutation tests, now complete hundreds or even thousands of times as quickly, and even the most trivial operations tend to be 5-10x faster due to I/O improvements.

We hasten to add that the vast majority of ideas contributing to PLINK 1.9's performance were developed elsewhere; in several cases, we have simply ported little-known but outstanding implementations without significant further revision (even while possibly uglifying them beyond recognition; sorry about that, Roman...). See the credits page for a partial list of people to thank. On a related note, if you are aware of an implementation of a PLINK command which is substantially better what we currently do, let us know; we'll be happy to switch to their algorithm and give them credit in our documentation and papers.

Nearly unlimited scale 
The main genomic data matrix no longer has to fit in RAM, so bleeding-edge datasets containing tens of thousands of individuals with exome- or whole-genome sequence calls at millions of sites can be processed on ordinary desktops (and this processing will usually complete in a reasonable amount of time). In addition, several key individual x individual and variant x variant matrix computations (including the GRM mentioned below) can be cleanly split across computing clusters (or serially handled in manageable chunks by a single computer).

Command-line interface improvements
We've standardized how the command-line parser works, migrated from the original 'everything is a flag' design toward a more organized flags + modifiers approach (while retaining backwards compatibility), and added a thorough command-line help facility.

Additional functions
In 2009, GCTA didn't exist. Today, there is an important and growing ecosystem of tools supporting the use of genetic relationship matrices in mixed model association analysis and other calculations; our contributions are a fast, multithreaded, memory-efficient --make-grm-gz/--make-grm-bin implementation which runs on OS X and Windows as well as Linux, and a closer-to-optimal --rel-cutoff pruner.

There are other additions here and there, such as cluster-based filters which might make a few population geneticists' lives easier, and a coordinate-descent LASSO. New functions are not a top priority for now (reaching 95%+ backward compatibility, and supporting dosage/phased/triallelic data, are more important...), but we're willing to take time off from just working on the program core if you ask nicely.

Sunday, December 01, 2013

Height prediction from common DNA variants

Still early days but it's clear where this is heading. Note the design using an outlier (case) and normal (control) group.

See also Five years of GWAS discovery and Recent human evolution: European height.
Common DNA variants predict tall stature in Europeans
DOI 10.1007/s00439-013-1394-0 (Journal: Human Genetics)

Abstract Genomic prediction of the extreme forms of adult body height or stature is of practical relevance in several areas such as pediatric endocrinology and forensic investigations. Here, we examine 770 extremely tall cases and 9,591 normal height controls in a population-based Dutch European sample to evaluate the capability of known height-associated DNA variants in predicting tall stature. Among the 180 normal height-associated single nucleotide polymorphisms (SNPs) previously reported by the Genetic Investigation of ANthropocentric Traits (GIANT) genome-wide association study on normal stature, in our data 166 (92.2 %) showed directionally consistent effects and 75 (41.7 %) showed nominally significant association with tall stature, indicating that the 180 GIANT SNPs are informative for tall stature in our Dutch sample. A prediction analysis based on the weighted allele sums method demonstrated a substantially improved potential for predicting tall stature (AUC = 0.75; 95 % CI 0.72–0.79) compared to a previous attempt using 54 height-associated SNPs (AUC = 0.65). The achieved accuracy is approaching practical relevance such as in pediatrics and forensics. Furthermore, a reanalysis of all SNPs at the 180 GIANT loci in our data identified novel secondary association signals for extreme tall stature at TGFB2 (P = 1.8 × 10−13) and PCSK5 (P = 7.8 × 10−11) suggesting the existence of allelic heterogeneity and underlining the importance of fine analysis of already discovered loci. Extrapolating from our results suggests that the genomic prediction of at least the extreme forms of common complex traits in humans including common diseases are likely to be informative if large numbers of trait-associated common DNA variants are available. [ Italics mine ]
AUC = Area Under Curve for the ROC curve defined as in the figure below. An ideal predictor has AUC = 1.

Saturday, November 30, 2013

Feynman and the secret of magic

Lubos Motl seems to have taken offense at my last post: Feynman's Cognitive Style. This is a rather ironic outcome, given that I've been a "Feynman idolator" since I was in high school :-) In fact, I chose my college (Caltech), career, and even research specialization under his influence!

In the previous post, I noted that Feynman's cognitive profile was probably a bit lopsided -- he was stronger mathematically than verbally (these notions are ill-defined, but see the previous post and subsequent discussion). His research style was also influenced by an exceptional originality, creativity and stubborn streak of independence. Ultimately, this style may have led to greater contributions than if he had followed a more conventional path. But, it is nevertheless interesting to observe that his stubborn habit of ignoring the literature led to large gaps in his knowledge. (See earlier post for examples. Contrary to Lubos' impression I am not making fun of Feynman!) In Coleman's analysis below (taken from Gleick's Feynman biography -- the chapter on Genius), Feynman's refusal to read the literature is portrayed as a conscious choice, but I suspect it also had to do with cognitive profile, especially early in his career. Feynman often found it easier to invent his own solution to a problem than to understand someone else's published paper.

Lubos is upset that I might think that Schwinger was, at least in some ways, "smarter" than Feynman. Even so, Feynman is my hero, not Schwinger. Feynman had no rival in his generation when it came to originality and creativity. See also Success vs Ability and Out on the tail.

NYTimes: ... The generation coming up behind him, with the advantage of hindsight, still found nothing predictable in the paths of his thinking. If anything he seemed perversely and dangerously bent on disregarding standard methods. "I think if he had not been so quick people would have treated him as a brilliant quasi crank, because he did spend a substantial amount of time going down what later turned out to be dead ends," said Sidney Coleman, a theorist who first knew Feynman at Caltech in the 50's.

"There are lots of people who are too original for their own good, and had Feynman not been as smart as he was, I think he would have been too original for his own good," Coleman continued. "There was always an element of showboating in his character. He was like the guy that climbs Mont Blanc barefoot just to show that it can be done."

Feynman continued to refuse to read the current literature, and he chided graduate students who would begin their work on a problem in the normal way, by checking what had already been done. That way, he told them, they would give up chances to find something original.

"I suspect that Einstein had some of the same character," Coleman said. "I'm sure Dick thought of that as a virtue, as noble. I don't think it's so. I think it's kidding yourself. Those other guys are not all a collection of yo-yos. Sometimes it would be better to take the recent machinery they have built and not try to rebuild it, like reinventing the wheel. Dick could get away with a lot because he was so goddamn smart. He really could climb Mont Blanc barefoot."

Coleman chose not to study with Feynman directly. Watching Feynman work, he said, was like going to the Chinese opera. "When he was doing work he was doing it in a way that was just -- absolutely out of the grasp of understanding. You didn't know where it was going, where it had gone so far, where to push it, what was the next step. With Dick the next step would somehow come out of -- divine revelation."
The characterization below is one of my favorites. We all stand in awe of the magicians!
"There are two kinds of geniuses, the 'ordinary' and the 'magicians,' " wrote the mathematician Mark Kac. "An ordinary genius is a fellow that you and I would be just as good as, if we were only many times better. There is no mystery as to how his mind works. Once we understand what they have done, we feel certain that we, too, could have done it. It is different with the magicians. They are, to use mathematical jargon, in the orthogonal complement of where we are and the working of their minds is for all intents and purposes incomprehensible. Even after we understand what they have done, the process by which they have done it is completely dark. Richard Feynman is a magician of the highest caliber."

Wednesday, November 27, 2013

Feynman's cognitive style

Some interesting finds in this 1966 AIP oral history interview with Feynman.

I have always felt that Feynman was cognitively a bit "lopsided" -- much stronger mathematically than verbally. This might be partially responsible for his way of learning -- it was often easier for him to invent his own solution than to read through someone else's lengthy paper. (Personality factors such as his independent streak, and his strong creativity, also play a role.) But this sometimes left him with gaping holes in knowledge. In contrast, Schwinger had at age 17 an encyclopedic understanding of what was known about quantum electrodynamics -- he had read and mastered all of the literature as a high school kid!

This excerpt reveals that Feynman did not understand the conventional formulation of QED even after Dyson's paper proving the equivalence of the Feynman and Schwinger methods. (When someone explained the action of a creation operator on the vacuum, Feynman reportedly objected "How can you create an electon? It disagrees with conservation of charge!" :-)
... I was struggling gradually to learn. I mean, I had to learn something to prove the connection between my thing and the same thing. Dyson had done a great deal in that direction. That didn’t satisfy me because I couldn’t follow that. Dyson told me, when he wrote his paper, “Don’t bother to read it, there’s nothing in it that you don’t know, except that it proves it’s the same as what everybody else knows, but it doesn’t say anything different or do anything different than is in your paper. Nothing more in it,” he told me.

... Yeah, because I remember him telling me not to worry about the paper. It hadn’t anything in it, you see. ... But then I thought I had to understand the connection, for publication purposes and others. And I had a good opportunity, because Case sent me his theorem — the manuscript of a big paper that he was going to publish in the Physical Review, which had all the steps of the theorem. Now, I argued in the meantime with myself, in my usual physical way of arguing, and concluded for several physical reasons, by some examples and other things — simpler examples that weren’t so elaborate as the calculations I made — that it couldn’t be true that the two methods would give the same result. ... I prepared a letter in which I wrote the physical arguments. Then I decided, that isn’t going to convince him. Nobody pays any attention to physical arguments, no matter how good they are. I’ve got to find a mistake in the proof. But the proof has creation and annihilation operators and all kinds of stuff. So I went to some students, in particular Mr. Scalator who was only fair, but he understood. He had learned in a pedestrian way what it all meant, and he explained to me what the symbols meant. So I learned like a little child what all this was about, so I understood what the symbols that he was using in the paper meant, and I tried to follow the proof, and I learned enough to be able to do that kind of mathematics, see — for the first time. So I followed the whole thing through, and I found a mistake, a very simple algebraic error, in the proof. He commuted some things that didn’t commute and so on.
Feynman never carefully read either Schwinger or Tomonaga's work:
Weiner: How about Tomonaga’s work? When did you first hear of it?
Feynman: I don’t know when I first heard of it. The work itself, I never knew exactly what it was, and I don’t yet know precisely what it was.
Weiner: You read his paper?
Feynman: No.
Weiner: I mean, there’s one paper that is often cited —
Feynman: No. No. I don’t think I read the paper. But this must be understood — I don’t mean anything disparaging. If Schwinger hadn’t been in the front yard at Pocono, or next to me, I wouldn’t have known what he did either. I got the same as everybody else. If you can do it yourself, why learn how somebody else does it? So I don’t know precisely what the relation of Tomonaga’s and Schwinger’s work is or the relation of his and mine. I think the relation of Tomonaga’s work to my work is very small. I mean, I think he’s gone around much closer the direction that Schwinger went.
Weiner: I think it’s the general impression.
Feynman: But I don’t know the precise relationship of their work. But I believe, if I’m not mistaken, although you’ll have to ask Schwinger, that everything that Schwinger did he did without knowledge of what Tomonaga did. I hear, but I don’t know, that Tomonaga did a very great deal, and did essentially what Schwinger did, except perhaps for working on certain practical problems. I don’t know. That’s what I hear. But I don’t know. I’m sorry, that sounds stupid, but I have never looked into it, and I never read Schwinger’s paper in a comprehensible way. I don’t know what’s in that paper of Schwinger’s.
Weiner: Haven’t tried to read it?
Feynman: Never. Tried in the sense that I looked at it and I flipped the pages, because it’s too hard. I read it at a time when I didn’t even know what a creation-annihilation operator was. I read it — you probably can prove that by the fact that I refer to it in various places, and get certain formulas out of it — I read it in the same way that I talk to him. When something looks like something, I know that’s it, you know? But I didn’t follow all the steps. I never followed all the steps.
Weiner: But you did know, when you talked to him at Pocono, and then —
Feynman: I know Schwinger — that’s what I say, I must have read it in pieces and bits. I know what Schwinger did; I know more or less how he did it. ...

Feynman: Yes, because we talked together, we had the physical idea of what starts it, but there’s a difference from that and checking all the equations, ... I don’t know whether he really read mine in detail or not. But he knows what’s in it, and I know what’s in his, but I can’t tell you. Perhaps if I look at his paper carefully, I can see that I really did read it, you know? I mean, I’d have to have it and look at it and see if I did read it. That’s a good way to look. I doubt that I read it in detail. I doubt that I looked at all of the various complicated sub-things that he had to worry about, like what to do with the longitudinal waves — because I don’t think there’s any problem with the longitudinal waves. I couldn’t pay attention to such a thing, see? So I doubt that I’ve ever read the paper in any careful way like a student would try to learn it. I don’t believe I’ve ever done that.
Finally, an interesting conversation between Feynman and Oppenheimer concerning the covariant propagator and positrons as electrons moving backwards in time:
So I went to the Physics Society and gave this paper, and I wanted Professor Oppenheimer to hear it, and other people like that. I particularly wanted Oppenheimer to hear it because he often said that there wasn’t anything to it. He understood Schwinger’s and he didn’t understand mine. And I thought he would be at the meeting. I’d kind of half thought about him when I prepared it. When I went to the meeting, he wasn’t there, but I gave the paper, and then Weisskopf got up and said, “This paper is so important and unusual” and so on “that we ought to give the man more time to express his ideas.” ... Then I stepped down, and just at that moment, Oppenheimer came in and sat down in the chair just ahead of me. And he turned around and said, “What did you talk about?” I said, “The idea of electrons going backwards,” meaning positrons. He said, “Oh, I heard all that. Oh, yes,” he said, “I heard that stuff, right? That stuff I heard.” I said, “Yeah, you’ve heard it, but you’ve never understood it.” Now, the response to that was an invitation I found in the mail when I got back to Cornell, to come to Princeton to the Institute and explain all my ideas, in as many lectures as I wished, two a week, as long a time as I wanted, expenses to be paid by the Institute, and so on. He’s a very great man, I know. I mean, I understand him. We’re good friends. You know. I mean, it’s not enemies. I said that because I was trying to get something across to him, that he didn’t understand it. That was honest. He knew that if I were driven to say that that was true — you know what I mean — and it was worth learning. So I said that, and his response was very generous — any length of time I want, any conditions. So I went to the Institute of Advanced Study.
In his eulogy, Schwinger described Feynman as "... the outstanding intuitionist of our age ..." :-)

Note added: I recalled another anecdote related to this post. At his Pocono talk Feynman was repeatedly asked by Dirac "Is it unitary?" (referring to Feynman's diagram method deduced from the path integral). Unfortunately, Feynman did not seem sure what "unitary" meant and responded "perhaps it will become clear as we proceed..." (a trick he learned from an earlier Schwinger talk). Feynman also did not seem to know what an S-matrix was!

But is it unitary?  :-)

See follow up post: Feynman and the secret of magic.

Monday, November 25, 2013

Goldman v. Aleynikov

Michael Lewis on the Aleynikov-Goldman HFT matter. The article mentions that Goldman trailed other players like Citadel when Aleynikov was hired. The head of HFT at Citadel was (I believe) a contemporary of mine in grad school at Berkeley, who did his dissertation in string theory. Malyshev, the guy who hired Aleynikov from Goldman, had his own legal problems when he left Citadel.
Vanity Fair: ... Serge knew nothing about Wall Street. The headhunter sent him a bunch of books about writing software on Wall Street, plus a primer on how to make it through a Wall Street job interview, and told him he could make a lot more than the $220,000 a year he was making at the telecom. Serge felt flattered, and liked the headhunter, but he read the books and decided Wall Street wasn’t for him. He enjoyed the technical challenges at the giant telecom and didn’t really feel the need to earn more money. A year later the headhunter called him again. By 2007, IDT was in financial trouble. His wife, Elina, was carrying their third child, and they would need to buy a bigger house. Serge agreed to interview with the Wall Street firm that especially wanted to meet him: Goldman Sachs.

... And then Wall Street called. Goldman Sachs put Serge through a series of telephone interviews, then brought him in for a long day of face-to-face interviews. These he found extremely tense, even a bit weird. “I was not used to seeing people put so much energy into evaluating other people,” he said. One after another, a dozen Goldman employees tried to stump him with brainteasers, computer puzzles, math problems, and even some light physics. It must have become clear to Goldman (as it was to Serge) that he knew more about most of the things he was being asked than did his interviewers. At the end of the first day, Goldman invited him back for a second day. He went home and thought it over: he wasn’t all that sure he wanted to work at Goldman Sachs. “But the next morning I had a competitive feeling,” he says. “I should conclude it and try to pass it because it’s a big challenge.”

... He returned for another round of Goldman’s grilling, which ended in the office of one of the high-frequency traders, another Russian, named Alexander Davidovich. A managing director, he had just two final questions for Serge, both designed to test his ability to solve problems.

The first: Is 3,599 a prime number?

Serge quickly saw there was something strange about 3,599: it was very close to 3,600. He jotted down the following equations: 3599 = (3600 – 1) = (602 – 12) = (60 – 1) (60 + 1) = 59 times 61. Not a prime number.

The problem wasn’t that difficult, but, as he put it, “it was harder to solve the problem when you are anticipated to solve it quickly.” It might have taken him as long as two minutes to finish. The second question the Goldman managing director asked him was more involved—and involving. He described for Serge a room, a rectangular box, and gave him its three dimensions. “He says there is a spider on the floor and gives me its coordinates. There is also a fly on the ceiling, and he gives me its coordinates as well. Then he asked the question: Calculate the shortest distance the spider can take to reach the fly.” The spider can’t fly or swing; it can only walk on surfaces. The shortest path between two points was a straight line, and so, Serge figured, it was a matter of unfolding the box, turning a three-dimensional object into a one-dimensional surface, then using the Pythagorean theorem to calculate the distances. It took him several minutes to work it all out; when he was done, Davidovich offered him a job at Goldman Sachs. His starting salary plus bonus came to $270,000.

... One small example of the kind of problems Serge found: Goldman’s trading on the NASDAQ exchange. Goldman owned the lone (unmarked) building directly across the street from NASDAQ in Carteret, New Jersey. The building housed Goldman’s dark pool. When Serge arrived, 40,000 messages per second were flying back and forth between computers inside the two buildings. Proximity, he assumed, must offer Goldman Sachs some advantage—after all, why else buy the only building anywhere near the exchange? But when he looked into it he found that, to cross the street from Goldman to NASDAQ, a signal took five milliseconds, or nearly as much time as it took a signal to travel on the fastest network from Chicago to New York. “The theoretical limit [of sending a signal] from Chicago to New York is something like seven milliseconds,” says Serge. “Everything more than that is the friction caused by man.” The friction could be caused by physical distance—say, if the signal moving across the street in Carteret, New Jersey, traveled in something less direct than a straight line. It could be caused by computer hardware. (The top high-frequency-trading firms chuck out their old gear and buy new stuff every few months.) But it could also be caused by slow, clunky software—and that was Goldman’s problem. Their high-frequency-trading platform was designed, in typical Goldman style, as a centralized hub-and-spoke system. Every signal sent was required to pass through the mother ship in Manhattan before it went back out into the marketplace. “But the latency [the five milliseconds] wasn’t mainly due to the physical distance,” says Serge. “It was because the traffic was going through layers and layers of corporate switching equipment.” ...
In this last paragraph Aleynikov sounds more like Sakharov than a millionaire quant ;-)
“If the incarceration experience doesn’t break your spirit, it changes you in a way that you lose many fears. You begin to realize that your life is not ruled by your ego and ambition and that it can end any day at any time. So why worry? You learn that, just like on the street, there is life in prison, and random people get there based on the jeopardy of the system. The prisons are filled with people who crossed the law, as well as by those who were incidentally and circumstantially picked and crushed by somebody else’s agenda. On the other hand, as a vivid benefit, you become very much independent of material property and learn to appreciate very simple pleasures in life such as the sunlight and morning breeze.”

Sunday, November 24, 2013

Chomsky: At War With Asia

In an earlier post I mentioned that my introduction to Chomsky came not via linguistics, but through his book At War With Asia, discovered by accident in the Page House library at Caltech. The book had a striking cover image, shown below.

My reaction to the book was similar to that of this blogger:
... no Chomsky book affected me as much as At War With Asia. To me, it was the purest, most incandescent experience of receiving facts imbued with moral clarity arising out of a submerged moral outrage. Perhaps I was affected because during the events being described I was dealing with a bureaucracy intent to induct me into the US Army, to be fed into the meat grinder of the Vietnam War, for 1968 to 1970.

I have never read a clearer description of colonial management (how the “white men” controlled “the natives”) than Chomsky gives in At War With Asia. From it one understood how the British had ruled India, and it opened my eyes as to how the “white men” in the U.S. today rule “the natives” (the ethnic minorities and the low economic classes, including the “white trash”), by stoking inter-group tensions (between ethnic groups in the colonies of prior centuries, and between groups based on economic class, ethnicity, gender, and sexuality in today’s “homeland”).

The greater part of At War With Asia deals with the massive and barbaric US aerial bombardment of northern Laos, in the Plain Of Jars. ... Chomsky’s focus and passion were so intense in this book, and yet the language is kept so reasoned and calm, that the effect on me was as if I suddenly awoke to the fact that while I was walking through a quiet summer scene, beneath me a raging magma chamber was expanding to explode. Were the subject matter less dire, I would say this book was pure poetry. In fact it was a restrained expression of a passionate — magmatic — compassion.

Chomsky is obviously a genius, a person born with great talent, and he is also a person of supreme dedication. ...
I also recommend the essay When Chomsky Wept, by Fred Branfman:
... we both had one of the most unique experiences of our lives — he on the back of my motorcycle, me driving him about the streets of Vientiane, as he sought to learn as much as he could about U.S. war-making in Laos, still at that point largely unknown to the world outside. It was only in the next month that Richard Nixon finally admitted for the first time that the U.S. had been bombing Laos for the previous six years, though he and Henry Kissinger continued to lie by claiming that the bombing was only striking military targets.

I have a number of particularly vivid memories of Noam from our week together. One was watching him read a newspaper. He would gaze at a page, seem to memorize it, and then a second later turn it and gaze at the next page. On one occasion I gave him a 500-page book to read on the war in Laos at about 10 at night, and met him the next morning at breakfast prior to our visit to political officer Jim Murphy at the U.S. Embassy. During the interview the issue of the number of North Vietnamese troops in Laos came up. The Embassy claimed that 50,000 had invaded Laos, when the evidence clearly showed there were no more than a few thousand. I almost fell off my chair when Noam quoted a footnote making that point, several hundred pages in, from the book I had given him the night before. I had heard the term “photographic memory” before. But I had never seen it so much in action, or put to such good use. (Interestingly enough, Jim showed Noam internal Embassy documents also confirming the lower number, which Noam later cited in his long chapter on Laos in “At War With Asia.”)

I was also struck by his self-deprecation. He had a near-aversion to talking about himself — contrary to most of the “Big Foot” journalists I had met. He had little interest in small talk, gossip or discussion of personalities, and was focused almost entirely on the issues at hand. He downplayed his linguistic work, saying it was unimportant compared to opposing the mass murder going on in Indochina. He had no interest whatsoever in checking out Vientiane’s notorious nightlife, tourist sites or relaxing by the pool. He was clearly driven, a man on a mission. He struck me as a genuine intellectual, a guy who lived in his head. And I could relate. I also lived in my head, and had a mission.

But what most struck me by far was what occurred when we traveled out to a camp that housed refugees from the Plain of Jars. I had taken dozens of journalists and other folks out to the camps at that point, and found that almost all were emotionally distanced from the refugees’ suffering. Whether CBS’s Bernard Kalb, NBC’s Welles Hangen, or the New York Times’ Sidney Schanberg, the journalists listened politely, asked questions, took notes and then went back to their hotels to file their stories. They showed little emotion or interest in what the villagers had been through other than what they needed to write their stories. Our talks in the car back to their hotels usually concerned either dinner that night or the next day’s events.

I was thus stunned when, as I was translating Noam’s questions and the refugees’ answers, I suddenly saw him break down and begin weeping. I was struck not only that most of the others I had taken out to the camps had been so defended against what was, after all, this most natural, human response. It was that Noam himself had seemed so intellectual to me, to so live in a world of ideas, words and concepts, had so rarely expressed any feelings about anything. I realized at that moment that I was seeing into his soul. And the visual image of him weeping in that camp has stayed with me ever since. When I think of Noam this is what I see.

One of the reasons his reaction so struck me was that he did not know those Laotians. It was relatively easy for me, having lived among them and loved people like Paw Thou so much, to commit to trying to stop the bombing. But I have stood in awe not only of Noam, but of the many thousands of Americans who spent so many years of their lives trying to stop the killing of Indochinese they did not know in a war they never saw.

As we drove back from the camp that day, he remained quiet, still shaken by what he had learned. He had written extensively of U.S. war-making in Indochina before this. But this was the first time he had met its victims face-to-face. And in the silence, an unspoken bond that we have never discussed was forged between us. ...
Let me qualify this post by noting that some of Chomsky's writing on other topics seems simply crazy to me. But on Vietnam and Laos he was right.

Sven Magnus Øen Carlsen

I am curious about what serious chess players think of Elo scores across generations -- is there a Flynn Effect? Current world champ Magnus Carlsen has the highest score of all time. It seems possible that due to computer training today's players are much better than those of the past -- we'll never know how giants like Bobby Fischer would have developed using today's methods. By Elo score Fischer is only 14th on the all-time list!

I thought interest in chess would decline after Deep Blue defeated Kasparov. But apparently the game is still thriving.

The excerpts below are from an old interview in Der Spiegel:
Carlsen: ... my success mainly has to do with the fact that I had the opportunity to learn more, more quickly. It has become easier to get hold of information. The players from the Soviet Union used to be at a huge advantage; in Moscow they had access to vast archives, with countless games carefully recorded on index cards. Nowadays anyone can buy this data on DVD for 150 euros; one disk holds 4.5 million games. There are also more books than there used to be. And then of course I started working with a computer earlier than Vladimir Kramnik or Viswanathan Anand.

SPIEGEL: When exactly?

Carlsen: I was eleven or twelve. I used the computer to prepare for tournaments, and I played on the Internet. Nowadays, children start using a computer at an even earlier age; they are already learning the rules on screen. In that sense I am already old-fashioned. Technological progress leads to younger and younger top players, everywhere in the world.

SPIEGEL: Is being young an advantage in modern chess?

Carlsen: As a young player you have a lot of energy, a lot of strength, you are very motivated. But young players are often not good at defending a position; they cannot cope well when fate turns against them. The fact is simply that experience is a central issue. One of the most important things in chess is pattern recognition: the ability to recognise typical themes and images on the board, characteristics of a position and their consequences. To a certain degree you can learn that while training, but there is nothing like playing routine. I have always made sure to get that. I am only 19, but I have certainly already played a thousand games in the classic style.
This is also interesting:
SPIEGEL: Mr Carlsen, what is your IQ?

Carlsen: I have no idea. I wouldn’t want to know it anyway. It might turn out to be a nasty surprise.

SPIEGEL: Why? You are 19 years old and ranked the number one chess player in the world. You must be incredibly clever.

Carlsen: And that’s precisely what would be terrible. Of course it is important for a chess player to be able to concentrate well, but being too intelligent can also be a burden. It can get in your way. I am convinced that the reason the Englishman John Nunn never became world champion is that he is too clever for that.

SPIEGEL: How that?

Carlsen: At the age of 15, Nunn started studying mathematics in Oxford; he was the youngest student in the last 500 years, and at 23 he did a PhD in algebraic topology. He has so incredibly much in his head. Simply too much. His enormous powers of understanding and his constant thirst for knowledge distracted him from chess.

SPIEGEL: Things are different in your case?

Carlsen: Right. I am a totally normal guy. My father is considerably more intelligent than I am.
Der Spiegel carefully tested Kasparov's IQ at 135, as discussed here. See also The Laskers and the Go master.

Friday, November 22, 2013

Chomsky animated

Chomsky on genetics and brainpower.

Chomsky on the po mo hustle.

My lunch with Chomsky:
I accidentally came across a copy of At War with Asia in the Page House library (Caltech) when I was a student. I had no idea who Chomsky was, I knew nothing yet of linguistics, but the book was powerful and affecting. Years later as a Junior Fellow I emailed Chomsky (a former Junior Fellow) at MIT and invited him to one of our formal Monday dinners. He declined to come to dinner, as his relationship with some of the senior fellows was contentious, but wanted to come to lunch and meet some of the younger people. We had a wonderful time, and I discovered he has a pretty good sense of humor :-)

Sunday, November 17, 2013


This looks like a huge development. Video. See also here, and this talk (audio) by Harvard graduate student Patrick Hsu (no relation; recent paper in Cell;

Independent (UK): Scientists are calling for a wider public debate on a new development in genetics that could allow the simple and accurate manipulation of the human genome, as revealed yesterday by The Independent.

The technique, known as CRISPR, could revolutionise human gene therapy and genetic engineering because it allows scientists for the first time to make the finest changes to the DNA of the chromosomes with relative ease.

One Nobel scientist, Craig Mello of the University of Massachusetts, said that the “jaw dropping” technique has the potential to transform the study and manipulation of genes and “lowers the barrier” to genetic engineering of human IVF embryos – something he would oppose.

Professor George Church of Harvard University, who was the first scientist to get the process working in human cells and mouse embryos, said that it was important to air the social and ethical implications of the technique to the wider public.

“Talking about the future is better than letting it sneak up on us. We need to do more of this or we will be left with very limited vocabulary in the space between positive and negative hype,” Professor Church said. ...

The CRISPR technique has developed rapidly since last year when Jennifer Doudna and her colleagues at the University of California, Berkeley, first demonstrated how it can be used in genetic engineering.

Scientists have since shown that it works well on human cells and mouse embryos and are talking about the possibility of refining it for gene therapy trials on patients with HIV and inherited disorders such as sickle-cell anaemia and Huntington’s disease.

Professor Dagan Wells, an IVF researcher at Oxford University, said that although there is still a long way to go before CRISPR could even be considered for use on IVF embryos, the technique could overcome many of the objections to permanently altering the germline of families affected by inherited disorders

“If the new method is as precise as has been suggested then concerns about inducing inadvertent, detrimental changes to the genome might start to subside. In that case, permanently fixing a lethal genetic defect might not seem so controversial,” Professor Wells said.

“However, I'm sure there will be some concern about the possibility that the technology could be used for 'enhancement' rather than repair, veering from medicine towards eugenics,” he warned. ...

The Toughest Leadership Job Of All

This is all true.
Forbes: ... Herman Wells, the former president of the University of Indiana, once observed that the ideal university president would combine “the physical charm of a Greek athlete, the cunning of Machiavelli, the wisdom of Solomon, the courage of a lion, the skin of a rhino … and the stomach of a goat.”

Being an effective corporate CEO isn’t that hard, really: Your biggest concern is ticking off your board; otherwise, you get to order underlings around and fire the ones you don’t like. What you say goes.

Being an effective university president involves much more diplomacy and persuasion and vision-selling. Yes, you are beholden to a board. But you have to lead through collaboration and cajoling, not control.

The most powerful group within a university is its tenured faculty. If they refuse to listen to you, you can’t fire them. That’s the whole idea behind academic freedom. But it makes moving in a new direction fraught with peril.

As one college president told me, “You don’t say, ‘Professor Smith, I need you to make this change.’ Instead, you say, “Professor Smith, I have a great idea I’d like to run past you. I really need your input in order to make this work, and I wonder if you have any thoughts about how to improve my idea and how to implement it?”

Can you imagine Steve Jobs saying that? Brilliant as he was, he’d last eight nano-seconds as the president of Stanford, MIT, Berkeley, USC, UCLA, Caltech or the other 50 to 100 research giants that fuel America’s economic and cultural preeminence.

The university president’s job is fantastically complex. Traditional companies open and shutter, and a founding CEO who fails can shrug it off and go on to start something new. But universities are expected to maintain high quality for centuries (consider how Oxford has kept churning for 8 centuries), while they’re also supposed to adapt to new developments (like online technology, globalization and so on). Give credit where credit is due: Apple’s a nice little enterprise, but Stanford will be thriving in 200 years, while Apple will be a historical footnote.

Not only does the university president need to cajole a bunch of people he can’t fire, he needs to convince others on the outside to contribute billions of dollars to fund his or her vision. That takes some special skill.

Warren Bennis, the great leadership guru (and a longtime mentor to me) who served for several years as university provost and a university president, wrote this a few years ago:

"No manner of leader, save possibly a mayor of a large city, deals with as vast and complicated a cartography of stakeholders as does the head of a major American research university. Speaking from personal experience, I can say that a university president is called on to be an entertainer, a visionary, a priest, a psychologist, and a CEO of 10 or 20 vastly different enterprises gathered under the seal of one university."

Saturday, November 16, 2013


A beautifully written short memoir from Ariel Levy in the New Yorker. I won't spoil it for you, but here's a sentence:
Sometimes, when I think about it, I still feel a dark hurt from some primal part of myself, and if I’m alone in my apartment when this happens I will hear myself making sounds that I never made before I went to Mongolia.
Levy (right) married Amy Norquist (left) in 2007:

At Berkeley

For more on Frederick Wiseman's new 4 hour documentary see here , here , here.
NYTimes: ... Mr. Wiseman has made his share of grim documentaries in which people are processed and oppressed by bureaucracy. “At Berkeley” is not one. Its cautiously upbeat attitude is expressed in a director’s note: “I think it is just as important for a filmmaker to show people of intelligence, character, tolerance and good will, hard at work, as it is to make movies about the failures, insensitivities and cruelties of others.” Amen.
For historical comparison, see below.

Trivia question: What do Chancellor Birgeneau (the leader of UC Berkeley in Wiseman's film) and Mario Savio, the leader of the Free Speech Movement, have in common?

Monday, November 11, 2013

Conspicuous consumption in the new gilded age

See also Credentialism and elite performance.
NYTimes: ... A silver spoon is no longer a mark of elite status. Take the nation’s top 10 percent of households. The top 1 percent — those making more than $394,000 annually — are today’s version of Veblen’s leisure class in terms of wealth, but they are not the biggest buyers of silver flatware. Instead, households in the rest of this high-earning cohort — those making between $114,000 and just under $394,000 — take the silver prize.

... Of course, when it comes to luxuries that can’t be faked, the top 1 percent are fervent spenders. Compared with the rest of the top 10 percent, they spend twice as much on college tuitions, three times as much on private elementary and high school tuitions and three times as much on tutoring to get their children into elite institutions. [ Italics Mine ]

... Veblen would recognize a profound difference between his leisure class and today’s top 1 percent. In his time, conspicuous consumption was largely frivolous. Buying silver spoons did not change a person’s life prospects; it only signaled high social rank. A university degree, another marker of social standing, was possible only for those with plenty of leisure time.

The conspicuous spending of today’s top 1 percent, by contrast, is purposeful. It affects one’s life chances. Most wealthy people work long hours, and the goal of much of their spending is to save time or make more money.

They spend heavily on education to ensure their children will have a sizable advantage in the future job market. A degree from an elite university, rather than connoting leisure time, is seen as an important career step. ...

Capital and Human Capital

According to this study of money managers, PhDs outperform on a risk adjusted basis, as do people who attended high SAT undergraduate institutions. MBAs do not outperform on a risk adjusted basis, but they take more risk.

See also The real big money is run by a physicist , The real smart guysA tale of two geeks.
What a Difference a Ph.D. Makes: More than Three Little Letters (

Abstract: Several hundred individuals who hold a Ph.D. in economics, finance, or others fields work for institutional money management companies. The gross performance of domestic equity investment products managed by individuals with a Ph.D. (Ph.D. products) is superior to the performance of non-Ph.D. products matched by objective, size, and past performance for one-year returns, Sharpe Ratios, alphas, information ratios, and the manipulation-proof measure MPPM. Fees for Ph.D. products are lower than those for non-Ph.D. products. Investment flows to Ph.D. products substantially exceed the flows to the matched non-Ph.D. products. Ph.D.s’ publications in leading economics and finance journals further enhance the performance gap.
An excerpt from the paper:
... The existing literature has explored some aspects of the link between managerial talent and both ability and education in the context of money management. For instance, Chevalier and Ellison (1999) find that mutual fund performance is related to certain educational characteristics of mutual fund managers. In particular, mutual fund managers graduating from undergraduate institutions with higher average SAT scores achieve higher raw fund returns. Similarly, Chevalier and Ellison (1999) also find that raw fund returns achieved by managers with an MBA outperform those without an MBA by 63 basis points per year. However, upon adjustments for risk, only the differential in risk-adjusted performance between the managers graduating from undergraduate institutions with higher average SAT scores and those graduating from undergraduate institutions with lower average SAT scores persists, whereas the risk-adjusted performance differential between funds managed by MBAs and non-MBAs disappears. ...
In this paper, we analyze the relation between investment performance of domestic equity products managed by institutional money manager and a broad spectrum of managers’ demonstrated academic ability. We focus on possession of a Ph.D. degree, as well as managers’ publication records in top outlets in economics and finance). Using gross returns (returns measured gross of fees, but net of transaction costs), we find that the performance of investment products managed by Ph.D.s is superior to the performance of non-Ph.D. products along several metrics widely employed to measure risk-adjusted product performance (objective-adjusted returns, Sharpe ratio, four-factor alpha, information ratio, and manipulation-proof performance measure). The performance differential in gross returns is preserved, even slightly enhanced, once fees are taken into account (fees for Ph.D. products tend to be slightly lower than fees for non-Ph.D. products).

Hiring employees to maximize assets under management is of first-order importance for money management companies. We find that net flows to Ph.D. products substantially exceed net flows to the non-Ph.D. products matched by style, assets under management, and recent performance. This difference is particularly accentuated in the top quintile of past performance. While the underlying cause of the relation between flows and educational attainment may ultimately stem from ability, knowledge, or soft skills, this finding provides a clear economic justification for the aggressive recruitment individuals holding a Ph.D. to serve in key positions in money management companies.

Finally, our analysis reveals that, among Ph.D. firms, a product’s performance is strongly positively related to the firm’s key personnel publication record in the top outlets in economics and finance. This finding indicates the extent to which proven academic ability at the highest percentiles of achievement translates into successful institutional money management.

Sunday, November 10, 2013

Skin jobs

45 minutes of deleted and alternate scenes. Lots of voice over from Harrison Ford with background information on the Blade Runner universe -- replicants, Tyrell Corporation, genetic designers, etc.

This is part of a long documentary on the making of Blade Runner.

I found the videos via this blog. The author shares some of my taste in movies -- he's also a fan of Whit Stillman (Metropolitan)!

Thursday, November 07, 2013

It came from the sky

What a great photo (see video). Also looks a bit like observers near a black hole!
NYTimes: When an asteroid exploded over the Russian city of Chelyabinsk in February, shattering windows for miles and injuring well over 1,000 people, experts said it was a rare event — of a magnitude that might occur only once every 100 to 200 years, on average.

But now a team of scientists is suggesting that the Earth is vulnerable to many more Chelyabinsk-size space rocks than was previously thought. In research being published Wednesday by the journal Nature, they estimate that such strikes could occur as often as every decade or two.

... A 450-foot-wide asteroid, Dr. Lu said, would be equivalent to 150 million tons of TNT. “You’re not going to wipe out humanity,” he said, “but if you get unlucky, you could kill 50 million people or you could collapse the world economy for a century, two centuries.”

Dr. Lu said astronomers had found only 10 to 20 percent of the near-Earth asteroids of that size.

Sentinel would also spot many smaller ones that could still be devastating. “What we’ve been talking about are the ones that would only destroy a major metropolitan area — all of New York City and the surrounding area,” Dr. Lu said.

He said only about 0.5 percent of these smaller asteroids, roughly the size of the 1908 one, have been found.

Because telescope surveys have counted so few of the small asteroids, Dr. Brown and his colleagues instead investigated what has actually hit the Earth. In one of the articles in Nature, they examined United States Air Force data from the 1960s and 1970s and later data from sensors verifying a ban on aboveground nuclear weapons testing.

The recordings captured the low-frequency atmospheric rumblings generated by about 60 asteroid explosions. Most came from small asteroids, but their data suggested that the somewhat larger ones hit more frequently than would be expected based on the estimates from sky surveys. That could mean the Earth has been unlucky recently, or that the estimates on the number of Chelyabinsk-size asteroids are too low.

“Any one of them individually I think you could dismiss,” Dr. Brown said, “but when you take it all together, I think the preponderance of the evidence is there is a much higher number of these tens-of-meters-size objects.”
Some ominous analysis here:
A 500-kiloton airburst over Chelyabinsk and an enhanced hazard from small impactors (Nature)

Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage1 than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects2. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave3, but owing to lack of observations this is uncertain4, 5. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×1012 joules). We show that a widely referenced technique4, 5, 6 of estimating airburst damage does not reproduce the observations, and that the mathematical relations7 based on the effects of nuclear weapons—almost always used with this technique—overestimate blast damage. This suggests that earlier damage estimates5, 6 near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques8, 9. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes. [ Italics mine ]

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