BioNetGMMFit: estimating parameters of a BioNetGen model from time-stamped snapshots of single cells.

Mechanistic models are commonly employed to describe signaling and gene regulatory kinetics in single cells and cell populations. Recent advances in single-cell technologies have produced multidimensional datasets where snapshots of copy numbers (or abundances) of a large number of proteins and mRNA are measured across time in single cells. The availability of such datasets presents an attractive scenario where mechanistic models are validated against experiments, and estimated model parameters enable quantitative predictions of signaling or gene regulatory kinetics.

Revisiting the Wald Test in Small Case-Control Studies With a Skewed Covariate.

The Wald test is routinely used in case-control studies to test for association between a covariate and disease. However, when the evidence for association is high, the Wald test tends to inflate small P values as a result of the Hauck-Donner effect (HDE). Here, we investigate the HDE in the context of genetic burden, both with and without additional covariates.

FREQMAX provides an alternative approach for determining high-resolution allele frequency thresholds in carrier screening.

As whole-genome data become available for increasing numbers of individuals across diverse populations, the list of genomic variants of unknown significance (VOUS) continues to grow. One powerful tool in VOUS interpretation is determining whether an allele is too common to be considered pathogenic. As genetic and epidemiological parameters vary across disease models, so too does the pathogenic allele frequency threshold for each disease gene.

Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice.

Aging in mammals is the gradual decline of an organism's physical, mental, and physiological capacity. Aging leads to increased risk for disease and eventually to death. Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice.

A new linear regression-like residual for survival analysis, with application to genome wide association studies of time-to-event data.

In linear regression, a residual measures how far a subject's observation is from expectation; in survival analysis, a subject's Martingale or deviance residual is sometimes interpreted similarly. Here we consider ways in which a linear regression-like interpretation is not appropriate for Martingale and deviance residuals, and we develop a novel time-to-event residual which does have a linear regression-like interpretation. We illustrate the utility of this new residual via simulation of a time-to-event genome-wide association study, motivated by a real study seeking genetic modifiers of Duchenne Muscular Dystrophy.

Prediction of short-term neonatal complications in preterm infants using exome-wide genetic variation and gestational age: a pilot study.

Background: Preterm birth is the leading cause of mortality and morbidity in young children, with over a million deaths per year worldwide arising from neonatal complications (NCs). NCs are moderately heritable although the genetic causes are largely unknown. Therefore, we investigated the impact of accumulated genetic variation (burden) on NCs in non-Hispanic White (NHW) and non-Hispanic Black (NHB) preterm infants.

Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats.

Respiratory syncytial virus (RSV) is a common virus that can have varying effects ranging from mild cold-like symptoms to mortality depending on the age and immune status of the individual. We combined mathematical modelling using ordinary differential equations (ODEs) with measurement of RSV infection kinetics in primary well-differentiated human bronchial epithelial cultures and in immunocompetent and immunosuppressed cotton rats to glean mechanistic details that underlie RSV infection kinetics in the lung. Quantitative analysis of viral titre kinetics in our mathematical model showed that the elimination of infected cells by the adaptive immune response generates unique RSV titre kinetic features including a faster timescale of viral titre clearance than viral production, and a monotonic decrease in the peak RSV titre with decreasing inoculum dose.

Replication, reanalysis, and gene expression: ME2 and genetic generalized epilepsy.

Objective: Genetic generalized epilepsy (GGE) consists of epileptic syndromes with overlapping symptoms and is considered to be largely genetic. Previous cosegregation and association studies have pointed to malic enzyme 2 (ME2) as a candidate susceptibility gene for adolescent-onset GGE. In this article, we present new evidence supporting ME2's involvement in GGE.

Lung Allocation Score Thresholds Prioritize Survival After Lung Transplantation.

Background: The lung allocation score (LAS) prioritizes lung transplant (LTx) candidates with poor transplant-free survival and expected survival benefit from LTx. Although patients with the highest LAS have the shortest waiting time, mortality benefit is unclear in this group, raising criticism that the LAS inappropriately prioritizes critically ill candidates. We aim to identify a threshold above which increasing LAS values do not predict increasing survival benefit.

Mutations in bacterial genes induce unanticipated changes in the relationship between bacterial pathogens in experimental otitis media.

Otitis media (OM) is a common polymicrobial infection of the middle ear in children under the age of 15 years. A widely used experimental strategy to analyse roles of specific phenotypes of bacterial pathogens of OM is to study changes in co-infection kinetics of bacterial populations in animal models when a wild-type bacterial strain is replaced by a specific isogenic mutant strain in the co-inoculating mixtures. As relationships between the OM bacterial pathogens within the host are regulated by many interlinked processes, connecting the changes in the co-infection kinetics to a bacterial phenotype can be challenging.

Predictive Utility of Lung Allocation Score for Retransplantation Outcomes.

Background: Treatment of primary graft failure after lung transplantation (LTx) may include retransplantation (rLTx). The number of rLTx cases has doubled since implementation of the Lung Allocation Score in 2005. The Lung Allocation Score was intended to predict LTx outcomes, but its predictive utility has not been assessed in rLTx.

Logistic Bayesian LASSO for detecting association combining family and case-control data.

Because of the limited information from the GAW20 samples when only case-control or trio data are considered, we propose eLBL, an extension of the Logistic Bayesian LASSO (least absolute shrinkage and selection operator) methodology so that both types of data can be analyzed jointly in the hope of obtaining an increased statistical power, especially for detecting association between rare haplotypes and complex diseases. The methodology is further extended to account for familial correlation among the case-control individuals and the trios. A 2-step analysis strategy was taken to first perform a genome-wise single single-nucleotide polymorphism (SNP) search using the Monte Carlo pedigree disequilibrium test (MCPDT) to determine interesting regions for the Adult Treatment Panel (ATP) binary trait.

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians.

Objective: Juvenile myoclonic epilepsy (JME) is a common adolescent-onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that BRD2 influences the expression of JME. The BRD2-JME connection is further corroborated by our murine model; Brd2 haploinsufficiency produces characteristics that typify the clinical hallmarks of JME.

Comparison of the Lund and Browder table to computed tomography scan three-dimensional surface area measurement for a pediatric cohort.

Background: Treating burns effectively requires accurately assessing the percentage of the total body surface area (%TBSA) affected by burns. Current methods for estimating %TBSA, such as Lund and Browder (L&B) tables, rely on historic body statistics. An increasingly obese population has been blamed for increasing errors in %TBSA estimates.

A Pragmatic Test for Detecting Association between a Dichotomous Trait and the Genotypes of Affected Families, Controls and Independent Cases.

The efficient analysis of hybrid designs [e.g., affected families, controls, and (optionally) independent cases] is attractive because it should have increased power to detect associations between genetic variants and disease.

Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry.

Objective: Screening for specific coding mutations in the EFHC1 gene has been proposed as a means of assessing susceptibility to juvenile myoclonic epilepsy (JME). To clarify the role of these mutations, especially those reported to be highly penetrant, we sought to measure the frequency of exonic EFHC1 mutations across multiple population samples.

Methods: To find and test variants of large effect, we sequenced all EFHC1 exons in 23 JME and 23 non-JME idiopathic generalized epilepsy (IGE) Hispanic patients, and 60 matched controls.

PedMIDAS-based scoring underestimates migraine disability on non-school days.

Objective: The aim of this study is to compare daily Pediatric Migraine Disability Assessment (PedMIDAS)-based scores for headaches occurring on school days vs non-school days and during the school year vs the summer holiday.

Background: The PedMIDAS is the only instrument validated to assess migraine disability among school-aged children. However, the PedMIDAS may underestimate disability during prolonged school holidays.

Increasing the power of association studies with affected families, unrelated cases and controls.

When studying the genetics of inherited diseases, researchers often collect data on affected families, unrelated cases, and healthy controls. However, the joint analysis of such heterogeneous data is difficult, and the simpler analysis of homogeneous subsets is often suboptimal. For example, while case-control tests of association are sensitive to allele frequency differences, the preferential transmission of risk alleles from heterozygous parents to their affected offspring is typically ignored.

Obtaining accurate p values from a dense SNP linkage scan.

A major concern of resequencing studies is that the pathogenicity of most mutations is difficult to predict. To address this concern, linkage (i.e.

How should we be searching for genes for common epilepsy? A critique and a prescription.

Despite enormous data collection and analysis efforts, the genetic influences on common epilepsies remain mostly unknown. We propose that reasons for the lack of progress can be traced to three factors: (1) A reluctance to consider fine-grained phenotype definitions based on extensive and carefully collected clinical data; (2) the pursuit of genetic analysis methods that are popular but poorly conceived and are inadequate to the task of resolving the problems inherent in common disease studies; (3) preconceived ideas about the genetic mechanisms that cause epilepsy (which we have discussed elsewhere). We propose a paradigm for finding epilepsy-related loci and alleles that has proven successful in other common diseases.

Finding disease genes: a fast and flexible approach for analyzing high-throughput data.

Linkage disequilibrium (LD) is the non-random distribution of alleles across the genome, and it can create serious problems for modern linkage studies. In particular, computational feasibility is often obtained at the expense of power, precision, and/or accuracy. In our new approach, we combine linkage results over multiple marker subsets to provide fast, efficient, and robust analyses, without compromising power, precision, or accuracy.

Multiple subsampling of dense SNP data localizes disease genes with increased precision.

Background/aims: Current linkage studies detect and localize trait loci using genotypes sampled at hundreds of thousands of single nucleotide polymorphisms (SNPs). Such data should provide precise estimates of trait location once linkage has been established. However, correlations between nearby SNPs can distort the information about trait location.

Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension.

Background: Familial pulmonary arterial hypertension (FPAH) is a rare, autosomal-dominant, inherited disease with low penetrance. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in at least 70% of FPAH patients. However, the lifetime penetrance of these BMPR2 mutations is 10% to 20%, suggesting that genetic and/or environmental modifiers are required for disease expression.