Abstract With the establishment of large biobanks, discovery of single nucleotide variants (SNVs, also known as single nucleotide polymorphisms (SNVs)) associated with various phenotypes has accelerated. An open question is whether genome-wide significant SNVs identified in earlier genome-wide association studies (GWAS) are replicated in later GWAS conducted in biobanks. To address this, we examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, “replication” GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNVs (of which 6289 reached P < 5e−8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0%; although lower for binary than quantitative phenotypes (58.1% versus 94.8% respectively). There was a 18.0% decrease in SNV effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNV effect size, phenotype trait (binary or quantitative), and discovery P value, we built and validated a model that predicted SNV replication with area under the Receiver Operator Curve = 0.90. While non-replication may reflect lack of power rather than genuine false-positives, these results provide insights about which discovered associations are likely to be replicated across subsequent GWAS.
This paper describes an efficient way of simulating the effects of device random mismatch on circuit transient characteristics, such as variations in delay or in frequency. The proposed method models DC random offsets as equivalent AC pseudo-noises and leverages the fast, linear periodically time-varying (LPTV) noise analysis available from RF circuit simulators. Therefore, the method can be considered as an extension to DCMATCH analysis and offers a large speed-up compared to the traditional Monte Carlo analysis. Although the assumed linear perturbation model is valid only for small variations, it enables easy ways to estimate correlations among variations and identify the most sensitive design parameters to mismatch, all at no additional simulation cost. Three benchmarks measuring the variations in the input offset voltage of a clocked comparator, the delay of a logic path, and the frequency of an oscillator demonstrate the speed improvement of about 100-1000× compared to a 1000-point Monte Carlo method.
A principled statistical segmentation of fruit fly walking leads to a compact model of immediate actions that can reproduce the unique behavioral sequences of individual flies.
This paper describes a dual delay-locked loop architecture which achieves low jitter, unlimited (modulo 2/spl pi/) phase shift, and large operating range. The architecture employs a core loop to generate coarsely spaced clocks, which are then used by a peripheral loop to generate the main system clock through phase interpolation. The design of an experimental prototype in a 0.8-/spl mu/m CMOS technology is described. The prototype achieves an operating range of 80 kHz-400 MHz. At 250 MHz, its peak-to-peak jitter with quiescent supply is 68 ps, and its jitter supply sensitivity is 0.4 ps/mV.
The authors summarize their experience in the conduct of meta-analysis of individual participants' data (MIPD) with time-to-event analyses in the field of genetic epidemiology. The MIPD offers many advantages compared with a meta-analysis of the published literature. These include standardization of case definitions, outcomes, and covariates; inclusion of updated information; the ability to fully test the assumptions of time-to-event models; better control of confounding; standardization of analyses of genetic loci that are in linkage disequilibrium; evaluation of alternative genetic models and multiple genes; consistent treatment of subpopulations; assessment of sampling bias; and the establishment of an international collaboration with the capability to prospectively update the meta-analyses and synthesize new information on multiple genetic loci and outcomes. The disadvantages of a MIPD compared with a meta-analysis of the published literature are that a much greater commitment of time and resources is required to collect primary data and to coordinate a large collaborative project. An MIPD may collect additional, unpublished data, but it is possible that not all published data may be contributed at the individual level. For questions that justify the required intensive effort, the MIPD method is a useful tool to help clarify the role of candidate genes in complex human diseases.
Citation metrics are widely used and misused. We have created a publicly available database of 100,000 top-scientists that provides standardized information on citations, h-index, co-authorship adjusted hm-index, citations to papers in different authorship positions and a composite indicator. Separate data are shown for career-long and single year impact. Metrics with and without self-citations and ratio of citations to citing papers are given. Scientists are classified into 22 scientific fields and 176 sub-fields. Field- and subfield-specific percentiles are also provided for all scientists who have published at least 5 papers. Career-long data are updated to end-of-2017 and to end-of-2018 for comparison.
Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines--seasonal, H5N1 and 2009 (H1N1)--in various age-classes (healthy children, adults or elderly). These meta-analyses have often adopted different analyses and study selection criteria. Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic reviews, we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings (or their interpretation) across previously published meta-analyses. For each age group, we performed analyses that included all trials that had been included in at least one relevant meta-analysis, also exploring whether effect sizes changed over time. Although we identified several discrepancies among the meta-analyses on seasonal vaccines for children and elderly, overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases. The available evidence on parenteral inactivated vaccines for children aged < 2 y remains scarce. Pre-pandemic "avian" H5N1 and pandemic 2009 (H1N1) vaccines can achieve satisfactory immunogenicity, but no meta-analysis has addressed H1N1 vaccination impact on clinical outcomes. Data on harms are overall reassuring, but their value is diminished by inconsistent reporting.
Citation metrics are increasingly used to appraise published research. One challenge is whether and how to normalize these metrics to account for differences across scientific fields, age (year of publication), type of document, database coverage, and other factors. We discuss the pros and cons for normalizations using different approaches. Additional challenges emerge when citation metrics need to be combined across multiple papers to appraise the corpus of scientists, institutions, journals, or countries, as well as when trying to attribute credit in multiauthored papers. Different citation metrics may offer complementary insights, but one should carefully consider the assumptions that underlie their calculation.
