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gwern branwen
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Meehl's 'crud factor': everything is correlated with everything; in this case, ultra-sensitive DNA forensic testing means you can pick up DNA from just about anybody, not just perpetrators.
Framed for Murder by His Own DNA
Framed for Murder by His Own DNA
themarshallproject.org
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"Nocebo effects with antidepressant clinical drug trial placebos", Reeves et al 2007 https://www.dropbox.com/s/gc89vdielmi7g59/2007-reeves.pdf?dl=0

"We describe an individual who experienced unusual negative effects while taking a placebo during a clinical drug trial. A 26-year-old male took 29 inert capsules, believing he was overdosing on an antidepressant. Subsequently, he experienced hypotension requiring intravenous fluids to maintain an adequate blood pressure until the true nature of the capsules was revealed. The adverse symptoms then rapidly abated. The nocebo effect (undesirable symptoms following administration of an inert substance that the patient believes to be an active drug) may have significant negative impacts on certain patients. Further research is warranted to better understand this phenomenon.
...Mr. A, a 26-year-old male, presented to the receiving clerk of an emergency department stating, 'Help me, I took all my pills' and then collapsed. As he fell, he dropped an empty prescription bottle. Assessment and treatment were initiated immediately. Mr. A was conscious but appeared drowsy and lethargic.
...After receiving 2 L of normal saline, blood pressure rose but again dropped when the infusion was slowed. Over 4 h, he was given approximately 6 L of fluid. He remained lethargic with a blood pressure of 100/62 and heart rate of 106. At this point, a physician from the clinical trial arrived and determined that Mr. A had taken placebos. When informed of this, the patient expressed surprise then almost tearful relief. Within 15 min, he was fully alert, blood pressure was 126/80, heart rate was 80.
...This issue may be of importance in clinical drug trials because some of the effects of an active drug and its placebo comparator may be due to the nocebo/placebo effect. Approximately one fourth of patients taking placebos report side effects [14]. The response of patients with depression to placebo is especially strong with antidepressant clinical trials consistently showing placebo response rates of 30% to 50%, drug response rates of 45% to 70% and a drug-placebo response difference of 18% to 25% [15]. An analysis of 19,636 subjects participating in antidepressant studies [16] revealed symptom reduction in 40.7% of patients receiving investigational drugs, in 41.7% of those receiving active antidepressant comparators and in 30.9% of those receiving placebo. A review of 19 antidepressant trials [17] found that placebo groups averaged 1.5 S.D. units of improvement, 75% of the overall progress shown by the drug groups, whose superiority over the placebo group was only 0.5 S.D.
...Loebel et al. [18] demonstrated lower than typically expected placebo response rates of 13.1% in patients with anxiety and 6.7% in depressed patients in one cohort during 1 week of placebo treatment as part of an ongoing clinical trial. They concluded that much lower rates of placebo response than are currently encountered may be possible among rigorously selected patients.
2007-reeves.pdf
2007-reeves.pdf
dropbox.com
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We're doing cat toys wrong: "Object play in adult domestic cats: the roles of habituation and disinhibition", Hall et al 2002: https://www.gwern.net/docs/catnip/2002-hall.pdf

"We have investigated the role of habituation and disinhibition in the control of object (predatory) play by adult domestic cats Felis silvestris catus both with and without prior experience of hunting. We hypothesised that object play is terminated by rapid habituation to the sensory characteristics of the object played with, and therefore should be disinhibited if the sensory characteristics of the object are changed. Three sequential sessions of play with an unchanging object (a toy) caused almost complete habituation of the play response; replacing the toy with one of contrasting colours in a fourth session elicited intense disinhibited play, suggesting that motivation for play itself had not diminished substantially during the first three sessions. The time interval between sessions affected the extent of disinhibition. After a long delay (25±45 min) between each session play was less intense in the fourth session than in the first; if the interval was 5 min, it was more intense, indicative of post- inhibitory rebound, possibly caused by initial positive feedback of play on its own performance. We suggest that object play by adult cats is controlled by two mechanisms derived from predatory behaviour: one responds to prey-like stimulus characteristics, such as texture and small size, which elicit play, while the second detects change in the toy. The behavioural default towards any object is initial interest if it possesses relevant stimulus characteristics, followed by rapid habituation unless these stimulus characteristics change."

Extended discussion by Bradshaw from Cat Sense 2013:

'My graduate student Sarah Hall and I found that habituation is the main underlying reason for this apparent boredom. We presented cats with toys - mouse-sized, fake-fur-covered "pillows" tied to a piece of cord - and at first they usually played intensely, appearing to treat the toy as if it was indeed a mouse.
However, many cats stopped playing within a matter of a couple minutes. When we took the toys away for a while and then presented them again, most of the cats started playing again, but neither as intensely nor for as long as the first time. By the third presentation, many of the cats would scarcely even begin to play. They clearly became "bored" with the toy.
If we switched the toy for a slightly different one - a different color (say, black to white, since cats' perception of colors is different from ours), texture, or odor - almost all of the cats would start playing again. Thus, they were "bored" not by the game, but by the toy itself. In fact, the frustration of being offered the same toy repeatedly actually increased their desire to play. If the interval between the last game with the original toy and the first game with the new toy was about five minutes, they attacked the second toy with even more vigor than they did the first one. 5 [Sarah L. Hall, John W. S. Bradshaw, and Ian Robinson, "Object Play in Adult Domestic Cats: The Roles of Habituation and Disinhibition", Applied Animal Behaviour Science 79 (2002): 263-71. https://www.gwern.net/docs/catnip/2002-hall.pdf Compared to "classic" habituation as studied in laboratory rats, the timescale over which cats remain habituated to toys is very long-minutes, rather than seconds. We subsequently found that the same applies to dogs.]
To understand why playing with a toy would make a cat frustrated, we considered what might motivate cats to play in the first place. Kittens sometimes play with toys as if they were fellow kittens, but adult cats invariably treat toys as if they were prey: they chase, bite, claw, and pounce on toys just as if the toys were mice or rats. To test the idea that cats think of toys in the same way they think of prey, we tried different kinds of toys to see which ones cats prefer. Our findings showed that, unsurprisingly, they like mouse-sized toys that are furry, feathered, or multi-legged-toy spiders, for example. Even indoor cats that had never hunted showed these preferences, so they must be hardwired in the cat's brain. The cats played with rat-sized toys covered in fake fur in a subtly different way from the mouse-sized toys. Instead of holding them in their front paws and biting them, most cats would hold the rat-sized toys at arm's length and rake them with their hind claws - just as hunting cats do with real rats. The cats were apparently thinking of their toys as if they were real animals, and as if their size, texture, and any simulated movement (such as our pulling on the toy's string) had triggered hunting instincts.
We then examined whether a cat's appetite has similar effects on the way it hunts and the way it plays with toys. If cats play with toys just for their own amusement, as many people assume they do, then they should be less inclined to play when they are hungry, since their minds should be focused instead on how to get something to eat. Conversely, as a hunting cat gets hungrier, it will hunt more intensely and become more inclined to take on larger prey than usual. We found exactly the latter when we offered toys to our cats. If their first meal of the day had been delayed, they played more intensely than usual with a mouse-sized toy - for example, biting it more frequently.
Moreover, many of the cats that normally refused to play with a rat-sized toy at all were now prepared to attack it. 6 This convinced us that adult cats do think that they are hunting when they're playing with toys.
Cats don't easily get "bored" with hunting, so we were still puzzled as to why our cats stopped playing with most toys so quickly. Indeed, they appeared to get "bored" with most commercially available toys and with the kinds of toys we made for our first experiments. The few toys that sustained our cats' interest all shared one quality: they fell apart as the cat was playing with them. 7 [Commercially available toys don't come apart for a good reason: occasionally a cat can choke on a piece of toy, or get fragments lodged in its gut.] Although we had to abandon experiments that involved these toys, which came apart at the seams as our cats batted them about, we noticed that several of the cats were extremely reluctant to give them up. We then realized that our original swapping experiments mimicked one aspect of what happens when a cat rips a toy apart: when we exchanged the toy for a slightly different one, the cat's senses told it that the toy had changed. It didn't seem to matter to the cat that it had not caused the change itself; what was important was that a change seemed to have occurred.
We deduced that not only do cats think they are hunting when they're playing with toys, but their behavior is being controlled by the same four mechanisms whether they're hunting or playing. One of these mechanisms is affected by hunger, and the same one that makes a cat more likely to play with a toy makes it likely to make a kill when it's hungry. 8 The second is triggered by the appearance - and presumably the smell and sound - of prey, and certain specific features, such as fur, feathers, and legs, that the cat recognizes instinctively are likely to belong to prey animals. The third mechanism is affected by the size of the toy or prey. Attacking a mouse puts the cat in much less danger than attacking a rat, so the cat attacks the rat much more carefully; likewise, cats treat large toys much more circumspectly than small toys, as if they were capable of fighting back. Even though cats should quickly learn that the toys are unlikely to retaliate, most cats don't seem to do so. The fourth mechanism is the source of the cat's apparent frustration: if all that biting and clawing doesn't seem to have any effect on its target, then either the target wasn't a meal, or if it is prey, then it's proving difficult to subdue. A toy that starts to disintegrate, or is taken away but looks different when it comes back (as in our original experiment), mimics the early stages of a kill, thus encouraging the cat to persist.'

Most cat toys don't change. Is this a serious problem? What about a color-changing moving ball? It could change colors and turn red when it 'dies'. It could then follow a different movement pattern when it comes 'back to life', cycling through a bunch of procedurally-generated patterns... Maybe something like a Sphero with different-colored LEDs in it?
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How often does correlation=causation? "Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey" https://www.bmj.com/content/352/bmj.i493 , Hemkens et al 2016:

"*Objective*: To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question.
Design: Meta-epidemiological survey.
Data sources: PubMed searched up to November 2014.
Methods: Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results.
Results: The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17,275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I^2^=0%)).
Conclusions: Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making."
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Principled GWAS leveraging genetic correlations using only public summary statistics for richer & more powerful GWAS: "Genomic SEM Provides Insights into the Multivariate Genetic Architecture of Complex Traits", Grotzinger et al 2018: https://www.biorxiv.org/content/early/2018/04/21/305029

"Methods for using GWAS to estimate genetic correlations between pairwise combinations of traits have produced 'atlases' of genetic architecture. Genetic atlases reveal pervasive pleiotropy, and genome-wide significant loci are often shared across different phenotypes. We introduce genomic structural equation modeling (Genomic SEM), a multivariate method for analyzing the joint genetic architectures of complex traits. Using formal methods for modeling covariance structure, Genomic SEM synthesizes genetic correlations and SNP-heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to identify variants with effects on general dimensions of cross-trait liability, boost power for discovery, and calculate more predictive polygenic scores. Finally, Genomic SEM can be used to identify loci that cause divergence between traits, aiding the search for what uniquely differentiates highly correlated phenotypes. We demonstrate several applications of Genomic SEM, including a joint analysis of GWAS summary statistics from five genetically correlated psychiatric traits. We identify 27 independent SNPs not previously identified in the univariate GWASs, 5 of which have been reported in other published GWASs of the included traits. Polygenic scores derived from Genomic SEM consistently outperform polygenic scores derived from GWASs of the individual traits. Genomic SEM is flexible, open ended, and allows for continuous innovations in how multivariate genetic architecture is modeled.
...We validate key properties of Genomic SEM with a series of simulations and illustrate the flexibility and utility of Genomic SEM with several analyses of real data. These include a joint analysis of GWAS summary statistics from five genetically correlated psychiatric case-control traits: schizophrenia, bipolar disorder, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety. We model genetic covariances among the traits using a general factor of psychopathology (p), for which we identify 27 independent SNPs not previously identified in the univariate GWASes, 5 of which can be validated based on separate GWASs. Polygenic scores derived using this p-factor consistently outperform polygenic scores derived from GWASs of the individual traits in out-of-sample prediction of psychiatric symptoms. Other demonstrations include a multivariate GWAS of neuroticism items, an exploratory factor analysis of anthropometric traits, and a simultaneous analysis of the unique genetic associations between schizophrenia, bipolar disorder, and educational attainment."

Aside from the scientific value, this will increase GWAS power considerably and importantly, can match the factor structure of traits like IQ - instead of dumb regression on a single crude number...
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"GWAS in 446,118 European adults identifies 78 genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates", Dashti et al 2018 https://www.biorxiv.org/content/early/2018/04/19/274977

"Sleep is an essential homeostatically-regulated state of decreased activity and alertness conserved across animal species, and both short and long sleep duration associate with chronic disease and all-cause mortality. Defining genetic contributions to sleep duration could point to regulatory mechanisms and clarify causal disease relationships. Through genome-wide association analyses in 446,118 participants of European ancestry from the UK Biobank, we discover 78 loci for self-reported sleep duration that further impact accelerometer-derived measures of sleep duration, daytime inactivity duration, sleep efficiency and number of sleep bouts in a subgroup (n=85,499) with up to 7-day accelerometry. Associations are enriched for genes expressed in several brain regions, and for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission, catecholamine production, synaptic plasticity, and unsaturated fatty acid metabolism. Genetic correlation analysis indicates shared biological links between sleep duration and psychiatric, cognitive, anthropometric and metabolic traits and Mendelian randomization highlights a causal link of longer sleep with schizophrenia."

"Genome-wide association analyses of chronotype in 697,828 individuals provides new insights into circadian rhythms in humans and links to disease", Jones et al 2018: https://www.biorxiv.org/content/early/2018/04/19/303941

"Using data from 697,828 research participants from 23andMe and UK Biobank, we identified 351 loci associated with being a morning person, a behavioural indicator of a person's underlying circadian rhythm. These loci were validated in 85,760 individuals with activity-monitor derived measures of sleep timing: the mean sleep timing of the 5% of individuals carrying the most "morningness" alleles was 25.1 minutes (95% CI: 22.5, 27.6) earlier than the 5% carrying the fewest. The loci were enriched for genes involved in circadian rhythm and insulin pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary (all FDR<1%). We provide some evidence that being a morning person was causally associated with reduced risk of schizophrenia (OR: 0.89; 95% CI: 0.82, 0.96), depression (OR: 0.94; 95% CI: 0.91, 0.98) and a lower age at last childbirth in women (β: -0.046 years; 95% CI: -0.067, -0.025), but was not associated with BMI (β: -4.6x10-4; 95% CI: -0.044, 0.043) or type 2 diabetes (OR: 1.00; 95% CI: 0.91, 1.1). This study offers new insights into the biology of circadian rhythms and disease links in humans."
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Unusual: "Phenomic selection: a low-cost and high-throughput alternative to genomic selection", Rincent et al 2018: https://www.biorxiv.org/content/early/2018/04/16/302117

"Genomic selection - the prediction of breeding values using DNA polymorphisms - is a disruptive method that has widely been adopted by animal and plant breeders to increase crop, forest and livestock productivity and ultimately secure food and energy supplies. It improves breeding schemes in different ways, depending on the biology of the species and genotyping and phenotyping constraints. However, both genomic selection and classical phenotypic selection remain difficult to implement because of the high genotyping and phenotyping costs that typically occur when selecting large collections of individuals, particularly in early breeding generations. To specifically address these issues, we propose a new conceptual framework called phenomic selection, which consists of a prediction approach based on low-cost and high-throughput phenotypic descriptors rather than DNA polymorphisms. We applied phenomic selection on two species of economic interest (wheat and poplar) using near-infrared spectroscopy on various tissues. We showed that one could reach accurate predictions in independent environments for developmental and productivity traits and tolerance to disease. We also demonstrated that under realistic scenarios, one could expect much higher genetic gains with phenomic selection than with genomic selection. Our work constitutes a proof of concept and is the first attempt at phenomic selection; it clearly provides new perspectives for the breeding community, as this approach is theoretically applicable to any organism and does not require any genotypic information."

Commentary: https://www.reddit.com/r/genomics/comments/8cz7fu/phenomic_selection_a_lowcost_and_highthroughput/dxiy4d0/
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Recent human evolution: Indonesian Bajau divers have recently evolved 50% larger spleens for storing reserve of oxygenated blood needed in long dives: "Physiological and Genetic Adaptations to Diving in Sea Nomads", Ilardo et al 2018 https://www.dropbox.com/s/w5t351hboh14ot3/2018-ilardo.pdf?dl=0 (Khan: https://www.gnxp.com/WordPress/2018/04/20/so-merfolk-are-a-real-thing-now/ )

"Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people (“Sea Nomads”) of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath-holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance."
2018-ilardo.pdf
2018-ilardo.pdf
dropbox.com
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A remarkable natural experiment: "Androgens and the Evolution of Male-Gender Identity among Male Pseudohermaphrodites with 5-alpha-reductase Deficiency", Imperato-McGinley et al 1979 https://www.dropbox.com/s/72yxy5e67pt5vl3/1979-imperatomcginley.pdf?dl=0

"To determine the contribution of androgens to the formation of male-gender identity, we studied male pseudohermaphrodites who had decreased dihydrotestosterone production due to 5 alpha-reductase deficiency. These subjects were born with female-appearing external genitalia and were raised as girls. They have plasma testosterone levels in the high normal range, show an excellent response to testosterone and are unique models for evaluating the effect of testosterone, as compared with a female upbringing, in determining gender identity. Eighteen of 38 affected subjects were unambiguously raised as girls, yet during or after puberty, 17 of 18 changed to a male-gender identity and 16 of 18 to a male-gender role. Thus, exposure of the brain to normal levels of testosterone in utero, neonatally and at puberty appears to contribute substantially to the formation of male-gender identity. These subjects demonstrate that in the absence of sociocultural factors that could interrupt the natural sequence of events, the effect of testosterone predominates, over-riding the effect of rearing as girls."
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