Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project

The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed “consensus calling,” to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.     

Genetic information improves the prediction of major adverse cardiovascular events in the GENEMACOR population

The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies.     

A tale of two defectors: the importance of standing for evolution of indirect reciprocity

Indirect reciprocity occurs when the cooperative behavior between two individuals is contingent on their previous behavior toward others. Previous theoretical analysis indicates that indirect reciprocity can evolve if individuals use an image-scoring strategy. In this paper, we show that, when errors are added, indirect reciprocity cannot be based on an image-scoring strategy. However, if individuals use a standing strategy, then cooperation through indirect reciprocity is evolutionarily stable. These two strategies differ with respect to the information to which they attend. While image-scoring strategies only need attend to the actions of others, standing strategies also require information about intent. We speculate that this difference may shed light on the evolvability of indirect reciprocity. Additionally, we show that systems of indirect reciprocity are highly sensitive to the availability of information. Finally, we present a model which shows that if indirect reciprocity were to evolve, selection should also favor trusting behavior in relations between strangers.     

Prevalence of zinc deficiency in junior high school students of Tehran City

Zinc deficiency is a health problem in many communities especially among adolescents because of pubertal growth sprout. This investigation was carried out to determine the epidemiology of zinc deficiency in junior high school students in Tehran City in 1997. This cross-sectional study was performed on 881 students (452 males and 429 females) with the mean age of 13.2±1.0 yr, who were selected by multistage random sampling method. Plasma, erythrocyte, and hair zinc levels were assayed by flame atomic absorption spectrophotometry. Anthropometric and demographic characteristics were measured and recorded on a questionnaire. Dietary intakes were evaluated by a 24-h recall method. Zinc deficiency was defined as having at least two indices from indices of erythrocyte, plasma, and hair zinc below 10 μg/mL, 100 μg/dL, and 125 μg/g of hair, respectively. The results showed that zinc deficiency prevalence was 31.1% (confidence interval: 28–34.4%). Zinc deficiency was 65%, 49%, and 1.3% based on plasma, erythrocyte, and hair zinc levels, respectively. The mean ± SD for plasma, erythrocyte, and hair zinc concentration, height-for-age, as well as weight-for-age Z scores were 95.2±17.7 μg/dL, 10.3±2.3 μg/mL, 239.4±54.4 μg/g, −0.40±0.92, and 0.12±0.91, respectively. As for dietary intake compared with the RDA, 50% of the subjects consumed less than 50% of their requirement for zinc RDA based on a 24-h dietary recall. Zinc intake in subjects was 7.5±3.7 μg, that in boys was higher than in girls. Correlation coefficients between zinc status indices were very weak. There was neither a linear nor nonlinear relationship between biochemical parameters and nutritional zinc intake. It is concluded that almost one-third to one-half of the subjects would be considered zinc deficient.     

The relationship between airborne pollen and fungal spore concentrations and seasonal pollen allergy symptoms in Cracow in 1997–1999

The investigation of airborne pollen and fungalspore concentrations was carried out in Cracowbetween 1997–1999. For this study thevolumetric method has been employed (Burkard).At the same time the clinical diagnosis ofpollen allergy in 40 patients was obtained onthe basis of an interview, positive skin pricktests with pollen extracts and increasedspecific IgE level. An increase in seasonalallergy symptoms in all patients occurred fromthe middle of May to the middle of August.Eighty eight percent of the patients (35 out of40) were sensitive to Poaceae pollen and about50% of them were additionally sensitive totree and herb pollen excluding grasses. Forpatients with additional allergy to tree pollenthe seasonal symptoms started at the end ofMarch (Betula) while for patients withadditional allergy to herb pollen it wasextended to the middle of September (Artemisia).Five people out of 40 revealed positive skinreactions to Alternaria spores and anincrease in specific IgE level. Positive skinreaction to Cladosporium spores with noincrease in specific IgE level occurred in 2patients. The increase in seasonal allergysymptoms in people sensitive to Alternariaspores noted in July and August could becaused not only by these spores but also byPoaceae pollen.     

Performance evaluation of a new algorithm for the detection of remote homologs with sequence comparison

A detailed analysis of the performance of hybrid, a new sequence alignment algorithm developed by Yu and coworkers that combines Smith Waterman local dynamic programming with a local version of the maximum-likelihood approach, was made to access the applicability of this algorithm to the detection of distant homologs by sequence comparison. We analyzed the statistics of hybrid with a set of nonhomologous protein sequences from the SCOP database and found that the statistics of the scores from hybrid algorithm follows an Extreme Value Distribution with lambda approximately 1, as previously shown by Yu et al. for the case of artificially generated sequences. Local dynamic programming was compared to the hybrid algorithm by using two different test data sets of distant homologs from the PFAM and COGs protein sequence databases. The studies were made with several score functions in current use including OPTIMA, a new score function originally developed to detect remote homologs with the Smith Waterman algorithm. We found OPTIMA to be the best score function for both both dynamic programming and the hybrid algorithms. The ability of dynamic programming to discriminate between homologs and nonhomologs in the two sets of distantly related sequences is slightly better than that of hybrid algorithm. The advantage of producing accurate score statistics with only a few simulations may overcome the small differences in performance and make this new algorithm suitable for detection of homologs in conjunction with a wide range of score functions and gap penalties.     

A retrospective assessment of the accuracy of the paternity inference program CERVUS

CERVUS is a Windows-based software package written to infer paternity in natural populations. It offers advantages over exclusionary-based methods of paternity inference in that multiple nonexcluded males can be statistically distinguished, laboratory typing error is considered and statistical confidence is determined for assigned paternities through simulation. In this study we use a panel of 84 microsatellite markers to retrospectively determine the accuracy of statistical confidence when CERVUS was used to infer paternity in a population of red deer (Cervus elaphus). The actual confidence of CERVUS-assigned paternities was not significantly different from that predicted by simulation.     

The impact of restrictive entry criterion during the placebo lead-in period

In the study of depression, most randomized clinical trials have design features that attempt to sample from a stable patient population. One commonly used design feature is to require patients to maintain some minimum baseline symptom severity score during a placebo lead-in period. One intent of this design feature is to evaluate the behavior of patients prior to administration of active medication. If, during the lead-in period, patients do not maintain minimum symptom severity, the patients are excluded from the remainder of the study, the theory being that the excluded patients are not part of a stable patient population and hence are not likely to demonstrate efficacy of a truly effective treatment. This presentation investigates the effectiveness of a restrictive entry criterion and proposes an alternative explanation for what is usually defined as placebo response.