Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats.
To present lessons learned about ...validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies.
The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University.
By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results.
Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.
Anecdotal and biographical reports have long suggested that bipolar disorder is more common in people with exceptional cognitive or creative ability. Epidemiological evidence for such a link is ...sparse. We investigated the relationship between intelligence and subsequent risk of hospitalisation for bipolar disorder in a prospective cohort study of 1,049,607 Swedish men. Intelligence was measured on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions over a mean follow-up period of 22.6 years was obtained from national records. Risk of hospitalisation with any form of bipolar disorder fell in a stepwise manner as intelligence increased (P for linear trend <0.0001). However, when we restricted analyses to men with no psychiatric comorbidity, there was a 'reversed-J' shaped association: men with the lowest intelligence had the greatest risk of being admitted with pure bipolar disorder, but risk was also elevated among men with the highest intelligence (P for quadratic trend=0.03), primarily in those with the highest verbal (P for quadratic trend=0.009) or technical ability (P for quadratic trend <0.0001). At least in men, high intelligence may indeed be a risk factor for bipolar disorder, but only in the minority of cases who have the disorder in a pure form with no psychiatric comorbidity.
Spin-Dependent WIMP Limits from a Bubble Chamber Behnke, E; Collar, J.I; Cooper, P.S ...
Science (American Association for the Advancement of Science),
02/2008, Letnik:
319, Številka:
5865
Journal Article
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Odprti dostop
Bubble chambers were the dominant technology used for particle detection in accelerator experiments for several decades, eventually falling into disuse with the advent of other techniques. We report ...here on a new application for these devices. We operated an ultraclean, room-temperature bubble chamber containing 1.5 kilograms of superheated CF₃I, a target maximally sensitive to spin-dependent and -independent weakly interacting massive particle (WIMP) couplings. An extreme intrinsic insensitivity to the backgrounds that commonly limit direct searches for dark matter was measured in this device under operating conditions leading to the detection of low-energy nuclear recoils like those expected from WIMPs. Improved limits on the spin-dependent WIMP-proton scattering cross section were extracted during our experiments, excluding this type of coupling as a possible explanation for a recent claim of particle dark-matter detection.
We describe here the design and initial implementation of the eMERGE‐PGx project. eMERGE‐PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research ...Network, has three objectives: (i) to deploy PGRNseq, a next‐generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1‐ to 3‐year time frame across several clinical sites; (ii) to integrate well‐established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record–based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site‐specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.
Clinical Pharmacology & Therapeutics (2014); 96 4, 482–489. doi:10.1038/clpt.2014.137
Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, ...and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.
BackgroundThere is growing evidence of an inverse association between intelligence (IQ) and unintentional injuries.MethodsAnalyses are based on a cohort of 1 109 475 Swedish men with IQ measured in ...early adulthood. Men were followed up for an average 24 years, and hospital admissions for unintentional injury were recorded.Results198 133 (17.9%) men had at least one hospital admission for any unintentional injury during follow-up. The most common cause of unintentional injury was falling, followed by road accidents, poisoning, fire and drowning. In addition, 14 637 (1.3%) men had at least one admission for complications of medical care. After adjusting for confounding variables, lower IQ scores were associated with an elevated risk of any unintentional injury (HR (95% CI) per SD decrease in IQ: 1.15 (1.14 to 1.15)) and of cause-specific injuries other than drowning (poisoning (1.53 (1.49 to 1.57)), fire (1.36 (1.31 to 1.41)), road traffic accidents (1.25 (1.23 to 1.26)), medical complications (1.20 (1.18 to 1.22)) and falling (1.17 (1.16 to 1.18))). These gradients were stepwise across the full IQ range.ConclusionsLow IQ scores in early adulthood were associated with a subsequently increased risk of unintentional injury. A greater understanding of mechanisms underlying these associations may provide opportunities and strategies for prevention.
Contrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue ...factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. "Classical" anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.
Oral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic ...inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.
The authors evaluated the little-examined association between intelligence (IQ) and injury mortality and, for the first known time, explored the extent to which IQ might explain established ...socioeconomic inequalities in injury mortality. A nationwide cohort of 1,116,442 Swedish men who underwent IQ testing at about 18 years of age was followed for mortality experience for an average of 22.6 years. In age-adjusted analyses in which IQ scores were classified into 4 groups, relative to the highest scoring category, the hazard ratio in the lowest was elevated for all injury types: poisonings (hazard ratio (HR) = 5.82, 95% confidence interval (CI): 4.25, 7.97), fire (HR = 4.39, 95% CI: 2.51, 7.77), falls (HR = 3.17, 95% CI: 2.19, 4.59), drowning (HR = 3.16, 95% CI: 1.85, 5.39), and road injury (HR = 2.17, 95% CI: 1.91, 2.47). Dose-response effects across the full IQ range were evident (P-trend < 0.001). Control for potential covariates, including socioeconomic position, had little impact on these gradients. When socioeconomic disadvantage—indexed by parental and subject's own occupational social class—was the exposure of interest, IQ explained a sizable portion (19%–86%) of the relation with injury mortality. These findings suggest that IQ may have an important role both in the etiology of injuries and in explaining socioeconomic inequalities in injury mortality.
Predicting plant–pollinator interaction networks over space and time will improve our understanding of how environmental change is likely to impact the functioning of ecosystems. Here we propose a ...framework for producing spatially explicit predictions of the occurrence and number of pairwise plant–pollinator interactions and of the species richness, diversity and abundance of pollinators visiting flowers. We call the framework ‘MetaComNet’ because it aims to link metacommunity dynamics to the assembly of ecological networks.
To illustrate the MetaComNet functionality, we used a dataset on bee–flower networks sampled at 16 sites in southeast Norway along with random forest models to predict bee–flower interactions. We included variables associated with climatic conditions (elevation) and habitat availability within a 250 m radius of each site. Regional commonness, site‐specific distance to conspecifics, social guild and floral preference were included as bee traits. Each plant species was assigned a score reflecting its site‐specific abundance, and four scores reflecting the bee species that the plant family is known to attract. We used leave‐one‐out cross‐validations to assess the models' ability to predict pairwise plant–bee interactions across the landscape.
The relationship between observed occurrence or absence of interactions and the predicted probability of interactions was nearly proportional (GLMlogistic regression slope = 1.09), matching the data well (AUC = 0.88), and explained 30% of the variation. Predicted probability of interactions was also correlated with the number of observed pairwise interactions (r = 0.32). The sum of predicted probabilities of bee–flower interactions were positively correlated with observed species richness (r = 0.50), diversity (r = 0.48) and abundance (r = 0.42) of wild bees interacting with plant species within sites.
Our findings show that the MetaComNet framework can be a useful approach for making spatially explicit predictions and mapping plant–pollinator interactions. Such predictions have the potential to identify areas where the pollination potential for wild plants is particularly high, and where conservation action should be directed to preserve this ecosystem function.
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