January 2018 gwern.net newsletter with 3 tech/philosophy essays and links on genetics, AI, biology/medicine, Bitcoin, linguistics, Touhou, and 2 anime reviews. newsletter 2017-12-21–2021-01-04finishedcertainty: logimportance: 0
Newsletter tag: archive of all issues back to 2013 for the gwern.net newsletter (monthly updates, which will include summaries of projects I’ve worked on that month (the same as the changelog), collations of links or discussions from my subreddit, and book/movie reviews.)
This page is a changelog for Gwern.net: a monthly reverse chronological list of recent major writings/changes/additions.
Following my writing can be a little difficult because it is often so incremental. So every month, in addition to my regular /r/Gwern subreddit submissions, I write up reasonably-interesting changes and send it out to the mailing list in addition to a compilation of links & reviews (archives).
A subreddit for posting links of interest and also for announcing updates to gwern.net (which can be used as a RSS feed). Submissions are categorized similar to the monthly newsletter and typically will be collated there.
Designed formal notations & distinct vocabularies are often employed in STEM fields, and these specialized languages are credited with greatly enhancing research & communication. Many philosophers and other thinkers have attempted to create more generally-applicable designed languages for use outside of specific technical fields to enhance human thinking, but the empirical track record is poor and no such designed language has demonstrated substantial improvements to human cognition such as resisting cognitive biases or logical fallacies. I suggest that the success of specialized languages in fields is inherently due to encoding large amounts of previously-discovered information specific to those fields, and this explains their inability to boost human cognition across a wide variety of domains.
Why are there so many places for backdoors and weird machines in your “computer”? Because your computer is in fact scores or hundreds, perhaps even thousands, of computer chips, many of which are explicitly or implicitly capable of Turing-complete computations (many more powerful than desktops of bygone eras), working together to create the illusion of a single computer. Backdoors, bugs, weird machines, and security do not care about what you think—only where resources can be found and orchestrated into a computation.
A classic cognitive bias in technological forecasting is motivated-stopping and lack of imagination in considering possibilities. Many people use a mental model of technologies in which they proceed in a serial sequential fashion and assume every step is necessary and only all together are they sufficient, and note that some particular step is difficult or unlikely to succeed and thus as a whole it will fail & never happen. But in reality, few steps are truly required. A technology only needs to succeed in one way to succeed, and to fail it must fail in all ways. There may be many ways to work around, approximate, brute force, reduce the need for, or skip entirely a step, or redefine the problem to no longer involve that step at all. Examples of this include the parallel projects used by the Manhattan Project & Apollo program, which reasoned that despite the formidable difficulties in each path to the end goal, at least one would work out—and they did. In forecasting, to counter this bias, one should make a strong effort to imagine all possible alternatives which could be pursued in parallel, and remember that overall failure requires all of them to fail.
Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (rg = 0.70). We used these findings as foundations for our use of a novel approach—multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)—to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination—as well as genes expressed in the synapse, and those involved in the regulation of the nervous system—may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.
Intelligence—the ability to learn, reason and solve problems—is at the forefront of behavioural genetic research. Intelligence is highly heritable and predicts important educational, occupational and health outcomes better than any other trait. Recent genome-wide association studies have successfully identified inherited genome sequence differences that account for 20% of the 50% heritability of intelligence. These findings open new avenues for research into the causes and consequences of intelligence using genome-wide polygenic scores that aggregate the effects of thousands of genetic variants.
Recent advances in genomics are producing powerful DNA predictors of complex traits, especially cognitive abilities. Here, we leveraged summary statistics from the most recent genome-wide association studies of intelligence and educational attainment to build prediction models of general cognitive ability and educational achievement. To this end, we compared the performances of multi-trait genomic and polygenic scoring methods. In a representative UK sample of 7,026 children at age 12 and 16, we show that we can now predict up to 11 percent of the variance in intelligence and 16 percent in educational achievement. We also show that predictive power increases from age 12 to age 16 and that genomic predictions do not differ for girls and boys. Multivariate genomic methods were effective in boosting predictive power and, even though prediction accuracy varied across polygenic scores approaches, results were similar using different multivariate and polygenic score methods. Polygenic scores for educational attainment and intelligence are the most powerful predictors in the behavioural sciences and exceed predictions that can be made from parental phenotypes such as educational attainment and occupational status.
Background: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.
Methods: Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.
In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution.
Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.
National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
BACKGROUND: Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.
METHODS: Retrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. 42 families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.
FINDINGS: The diagnostic sensitivity was 43% (18 of 42 infants) for rWGS and 10% (4 of 42 infants) for standard of care (p = 0.0005). The rate of clinical utility for rWGS (31%, 13 of 42 infants) was significantly greater than for standard of care (2%, one of 42; p = 0.0015). 11 (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In 6 of the 11 infants, the changes in management reduced inpatient cost by $800,000 to $2,000,000.
DISCUSSION: These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.
“Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways”, Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen Benjamins, Ana B. Muñoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Patrick F. Sullivan, Sophie van der Sluis, Tinca J.C. Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma (2018-01-30):
Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (n = 1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.
“Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps”, Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason M. Torres, N. William Rayner, Valgerdur Steinthorsdottir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael Preuss, Bram Peter Prins, Xiuqing Guo, Lawrence F. Bielak, DIAMANTE Consortium, Amanda J. Bennett, Jette Bork-Jensen, Chad M. Brummett, Mickaël Canouil, Kai-Uwe Eckardt, Krista Fischer, Sharon LR Kardia, Florian Kronenberg, Kristi Läll, Ching-Ti Liu, Adam E. Locke, Jian′an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Sch࿆nherr, Claudia Schurmann, Loïc Yengo, Erwin P. Bottinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, Jose C. Florez, Ian Ford, Oscar H. Franco, Timothy M. Frayling, Vilmantas Giedraitis, Sophie Hackinger, Andrew T. Hattersley, Christian Herder, M. Arfan Ikram, Martin Ingelsson, Marit E. Jørgensen, Torben Jørgensen, Jennifer Kriebel, Johanna Kuusisto, Symen Ligthart, Cecilia M. Lindgren, Allan Linneberg, Valeriya Lyssenko, Vasiliki Mamakou, Thomas Meitinger, Karen L. Mohlke, Andrew D. Morris, Girish Nadkarni, James S. Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Daniel R. Witte, Josée Dupuis, Patricia A. Peyser, Eleftheria Zeggini, Ruth J. F Loos, Philippe Froguel, Erik Ingelsson, Lars Lind, Leif Groop, Markku Laakso, Francis S. Collins, J. Wouter Jukema, Colin N. A Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Goncalo Abecasis, James B. Meigs, Jerome I. Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J. Wareham, Kari Stefansson, Anna L. Gloyn, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy (2018-01-09):
We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]<5%), identified 243 genome-wide significant loci (p<5×10−8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p<10−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF<5%) and 24 rare (MAF<0.5%) index SNPs at 60 loci, including 14 with estimated allelic OR>2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.
Human intelligence differences are linked to diverse cognitive abilities and predict important life outcomes. Here we investigate the biological bases of fluid intelligence in a large sample of participants from the UK Biobank. We explore the genetic underpinnings of fluid intelligence via genome-wide association analysis (N = 108,147), and examine brain morphological correlates of fluid intelligence (N = 7, 485). Importantly, we develop novel statistical methods that enable high-dimensional co-heritability analysis, and compute high-resolution surface maps for the co-heritability and genetic correlations between fluid intelligence and cortical thickness measurements. Our analyses reveal the genetic overlap between fluid intelligence and brain morphology in predominately left inferior precentral gyrus, pars opercularis, superior temporal cortex, supramarginal gyrus, and their proximal regions. These results suggest a shared genetic basis between fluid intelligence and Broca’s speech and Wernicke’s language areas and motor regions, and may contribute to our understanding of the biological substrate of human fluid intelligence.
Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabits territories under a wide range of temperatures. Focusing on cold perception – which is central to thermoregulation and survival in cold environments— we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analysed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent –precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today.
Some human populations were likely under strong pressure to adapt biologically to cold climates during their colonization of non-African territories in the last 50,000 years. Such putative adaptations required genetic variation in genes that could mediate adaptive responses to cold. TRPM8 is potentially one such gene, being the only known receptor for the sensation of moderate cold temperature. We show that a likely regulatory genetic variant nearby TRPM8 has several signatures of positive selection rising its frequency in Eurasian populations during the last 25,000 years. While the genetic variant was and is rare in Africa, it is now common outside of Africa, with frequencies that strongly correlate with latitude and are highest in northern European populations. Interestingly, this same genetic variant has previously been strongly associated with migraine. This suggests that adaptation to cold has potentially contributed to the variation in migraine prevalence that exists among human groups today.
This work details CipherGAN, an architecture inspired by CycleGAN used for inferring the underlying cipher mapping given banks of unpaired ciphertext and plaintext. We demonstrate that CipherGAN is capable of cracking language data enciphered using shift and Vigenere ciphers to a high degree of fidelity and for vocabularies much larger than previously achieved. We present how CycleGAN can be made compatible with discrete data and train in a stable way. We then prove that the technique used in CipherGAN avoids the common problem of uninformative discrimination associated with GANs applied to discrete data.
Birth order refers to the order a child is born in their family; first-born and second-born are examples. Birth order is often believed to have a profound and lasting effect on psychological development. This assertion has been repeatedly challenged. Recent research has consistently found that earlier born children score slightly higher on average on measures of intelligence, but has found zero, or almost zero, robust effect of birth order on personality. Nevertheless, the notion that birth-order significantly influences personality continues to have a strong presence in pop psychology and popular culture.
Persistent forms of nondual awareness, enlightenment, mystical experience, and so forth (Persistent Non-Symbolic Experience) have been reported since antiquity. Though sporadic research has been performed on them, the research reported here represents the initial report from the first larger scale cognitive psychology study of this population.
Method: Assessment of the subjective experience of fifty adult participants reporting persistent non-symbolic experience was undertaken using 6–12 hour semi-structured interviews and evaluated using thematic analysis. Additional assessment was performed using psychometric measures, physiological measurement, and experimentation.
Results: Five core, consistent categories of change were uncovered: sense-of-self, cognition, emotion, perception, and memory. Participants’ reports formed clusters in which the types of change in each of these categories were consistent. Multiple clusters were uncovered that formed a range of possible experiences. The variety of these experiences and their underlying categories may inform the debate between constructivist, common core, and participatory theorists.
…Over the course of a week, his father died followed very rapidly by his sister. He was also going through a significant issue with one of his children. Over dinner I asked him about his internal state, which he reported as deeply peaceful and positive despite everything that was happening. Having known that the participant was bringing his longtime girlfriend, I’d taken an associate researcher with me to the meeting to independently collect the observations from her. My fellow researcher isolated the participant’s girlfriend at the bar and interviewed her about any signs of stress that the participant might be exhibiting. I casually asked the same questions to the participant as we continued our dinner conversation. Their answers couldn’t have been more different. While the participant reported no stress, his partner had been observing many telltale signs: he wasn’t sleeping well, his appetite was off, his mood was noticeably different, his muscles were much tenser than normal, his sex drive was reduced, his health was suffering, and so forth…It was not uncommon for participants to state that they had gained increased bodily awareness upon their transition into PNSE. I arranged and observed private yoga sessions with a series of participants as part of a larger inquiry into their bodily awareness. During these sessions it became clear that participants believed they were far more aware of their body than they actually were…Many participants discussed the thought, just after their transition to PNSE, that they would have to go to work and explain the difference in themselves to co-workers. They went on to describe a puzzled drive home after a full day of work when no one seemed to notice anything different about them. Quite a few chose to never discuss the change that had occurred in them with their families and friends and stated that no one seemed to notice much of a difference.
There was also a progressively decreasing sense of agency. In the final stage, Location 4, he reports: “These participants reported having no sense of agency or any ability to make a decision. It felt as if life was simply unfolding and they were watching the process happen. Severe memory deficits were common in these participants, including the inability to recall scheduled events that were not regular and ongoing.” And yet, almost all of the subjects reported it as a positive experience. The subjects, at whatever point they were in the scale, were often completely certain about the nature of the experience: “PNSE was often accompanied by a tremendous sense of certainty that participants were experiencing a ‘deeper’ or ‘more true’ reality. As time passed, this often increased in strength.” They also tended to be dogmatic about their PNSE being the real thing (whichever location they were at) and descriptions of other people’s different PNSEs as not the real thing. Another way to say “completely certain” is “unable to doubt”.
Bitcoin has enjoyed wider adoption than any previous cryptocurrency; yet its success has also attracted the attention of fraudsters who have taken advantage of operational insecurity and transaction irreversibility. We study the risk investors face from the closure of Bitcoin exchanges, which convert between Bitcoins and hard currency. We examine the track record of 80 Bitcoin exchanges established between 2010 and 2015. We find that nearly half (38) have since closed, with customer account balances sometimes wiped out. Fraudsters are sometimes to blame, but not always. 25 exchanges suffered security breaches, 15 of which subsequently closed. We present logistic regressions using using longitudinal data on Bitcoin exchanges aggregated quarterly. We find that experiencing a breach is correlated with a 13-times greater odds that an exchange will close in that same quarter. We find that higher-volume exchanges are less likely to close (each doubling in trade volume corresponds to a 12 percent decrease in the odds of closure). We also find that exchanges who derive most of their business from trading less popular (fiat) currencies, which are offered by at most one competitor, are less likely to close.
The Ern Malley hoax, also called the Ern Malley affair, was Australia's most famous literary hoax. Its name derives from Ernest Lalor "Ern" Malley, a fictitious poet whose biography and body of work were created in one day in 1943 by conservative writers James McAuley and Harold Stewart in order to hoax the Angry Penguins, a modernist art and literary movement centered around a journal of the same name, co-edited by poet Max Harris and art patron John Reed, of Heide, Melbourne.
Kurozuka is a Japanese novel written by Baku Yumemakura. A manga adaptation was illustrated by Takashi Noguchi and it was serialized in the seinen manga magazine Oh Super Jump starting in 2003 by Shueisha and ended in December 2006. An anime adaptation by Madhouse was announced by Japanese anime television network Animax in May 2008 and ran between October and December 2008, spanning a total of 12 episodes.
Flip Flappers is a Japanese anime television series produced by Studio 3Hz and directed by Kiyotaka Oshiyama, with Yuniko Ayana providing the story concept, tanu serving as the concept artist, Takashi Kojima designing the characters and TO-MAS composing the music. It was first announced on March 25, 2016, at the AnimeJapan convention, and aired on AT-X and other networks between October and December 2016. The series is a science fiction adventure story that revolves around two heroines, Papika and Cocona.
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