Genetically meaningful phenotypic subgroups in autism spectrum disorders

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview‐Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38–1.42, P < 0.00001), and genotypes were more similar within subgroups compared to the unsubgrouped dataset (Fst = 0.17 ± 0.0.0009). These results suggest that the subgroups recapitulate genetic etiology. Using the same approach in an independent dataset from the Autism Genome Project, we similarly identified two distinct subgroups of cases and confirmed this severity‐based dichotomy. We also observed evidence for genetic contributions to subgroups identified in the replication dataset. Our results provide more effective methods of phenotype definition that should increase power to detect genetic factors influencing risk for ASD .     

An adaptive trial design to optimize dose-schedule regimes with delayed outcomes

This paper proposes a two-stage phase I-II clinical trial design to optimize dose-schedule regimes of an experimental agent within ordered disease subgroups in terms of the toxicity-efficacy trade-off. The design is motivated by settings where prior biological information indicates it is certain that efficacy will improve with ordinal subgroup level. We formulate a flexible Bayesian hierarchical model to account for associations among subgroups and regimes, and to characterize ordered subgroup effects. Sequentially adaptive decision-making is complicated by the problem, arising from the motivating application, that efficacy is scored on day 90 and toxicity is evaluated within 30 days from the start of therapy, while the patient accrual rate is fast relative to these outcome evaluation intervals. To deal with this in a practical manner, we take a likelihood-based approach that treats unobserved toxicity and efficacy outcomes as missing values, and use elicited utilities that quantify the efficacy-toxicity trade-off as a decision criterion. Adaptive randomization is used to assign patients to regimes while accounting for subgroups, with randomization probabilities depending on the posterior predictive distributions of utilities. A simulation study is presented to evaluate the design's performance under a variety of scenarios, and to assess its sensitivity to the amount of missing data, the prior, and model misspecification.     

Variability of esterase patterns in adult flies of the <Emphasis Type="Italic">saltans</Emphasis> species group of <Emphasis Type="Italic">Drosophila</Emphasis> (subgenus <Emphasis Type="Italic">Sophophora</Emphasis>)

Esterases are known for their involvement in several physiological processes and high degree of polymorphism, in many organisms. Such polymorphism has been used to characterize species and species groups and to study genetic changes occurred in their evolutionary history. In the present study, the esterase patterns of 19 strains from 10 species representative of the five subgroups of the saltans species group were analyzed using polyacrylamide gel electrophoresis and α- and β- naphthyl acetates as substrates. Fifty-one esterase bands were detected and classified as 31 α-esterases, 18 β-esterases and two α/β-esterases. On the basis of the inhibition patterns using Malathion and eserine sulfate, 34 bands were classified as carboxylesterases, 14 as acethylesterases and three as cholinesterases. Ten gene loci were tentatively established on the basis of data on band position in the gel, substrate preference and inhibition pattern. Twenty bands were species-specific, the remaining being shared by species from the same or different subgroups. Bands detected exclusively in males and bands with a different frequency or degree of expression between sexes were also detected. In the gels prepared for analysis of gene expression in the body parts (head, thorax and abdomen), the degree of expression of the β-esterases was higher in the thorax, while the α-esterases were expressed predominantly in the abdomen and thorax. A global view of the data available at present on the esterases of the species from the saltans group and their degree of polymorphism are presented, as well as the possibility of using some β-esterases, because of their characteristics in the gels, as markers for species identification.