New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD.

Statistical power calculations inform the design and interpretation of genetic association studies, but few programs are tailored to case-control studies of single nucleotide polymorphisms (SNPs) in unrelated subjects. We have developed the "Power for Genetic Association analyses" (PGA) package which comprises algorithms and graphical user interfaces for sample size and minimum detectable risk calculations using SNP or haplotype effects under different genetic models and study constrains. The software accounts for linkage disequilibrium and statistical multiple comparisons. The results are presented in graphs or tables and can be printed or exported in standard file formats. PGA is user friendly software that can facilitate decision making for association studies of candidate genes, fine-mapping studies, and whole-genome scans. Stand-alone executable files and a Matlab toolbox are available for download at: http://dceg.cancer.gov/bb/tools/pga

The genetic basis of odorant-specific variations in human olfactory thresholds, and in particular of enhanced odorant sensitivity (hyperosmia), remains largely unknown. Olfactory receptor (OR) segregating pseudogenes, displaying both functional and nonfunctional alleles in humans, are excellent candidates to underlie these differences in olfactory sensitivity. To explore this hypothesis, we examined the association between olfactory detection threshold phenotypes of four odorants and segregating pseudogene genotypes of 43 ORs genome-wide. A strong association signal was observed between the single nucleotide polymorphism variants in OR11H7P and sensitivity to the odorant isovaleric acid. This association was largely due to the low frequency of homozygous pseudogenized genotype in individuals with specific hyperosmia to this odorant, implying a possible functional role of OR11H7P in isovaleric acid detection. This predicted receptor–ligand functional relationship was further verified using the Xenopus oocyte expression system, whereby the intact allele of OR11H7P exhibited a response to isovaleric acid. Notably, we also uncovered another mechanism affecting general olfactory acuity that manifested as a significant inter-odorant threshold concordance, resulting in an overrepresentation of individuals who were hyperosmic to several odorants. An involvement of polymorphisms in other downstream transduction genes is one possible explanation for this observation. Thus, human hyperosmia to isovaleric acid is a complex trait, contributed to by both receptor and other mechanisms in the olfactory signaling pathway. Humans can accurately discern thousands of odors, yet there is considerable inter-individual variation in the ability to detect different odors, with individuals exhibiting low sensitivity (hyposmia), high sensitivity (hyperosmia), or even “blindness” (anosmia) to particular odors. Such differences are thought to stem from genetic differences in olfactory receptor (OR) genes, which encode proteins that initiate olfactory signaling. OR segregating pseudogenes, which have both functional and inactive alleles in the population, are excellent candidates for producing this olfactory phenotype diversity. Here, we provide evidence that a particular segregating OR gene is related to sensitivity to a sweaty odorant, isovaleric acid. We show that hypersensitivity towards this odorant is seen predominantly in individuals who carry at least one copy of the intact allele. Furthermore, we demonstrate that this hyperosmia is a complex trait, being driven by additional factors affecting general olfactory acuity. Our results highlight a functional role of segregating pseudogenes in human olfactory variability, and constitute a step towards deciphering the genetic basis of human olfactory variability.

It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core symptoms. Here, we quantified Longitudinal changes in core autism spectrum disorder symptoms of 131 children diagnosed at 1.2–5 years of age using the Autism Diagnostic Observation Schedule–Second Edition Calibrated Severity Scores over a 1-2 year period. We examined the prevalence and magnitude of Calibrated Severity Scores changes across children who were diagnosed at different ages. The results revealed that age of diagnosis was significantly correlated with poorer outcome ( r(129) = 0.41, p < 0.001). Approximately 65% of the children diagnosed before 2.5 years of age exhibited improvements in Autism Diagnostic Observation Schedule–Second Edition Calibrated Severity Scores (⩾2 points) in contrast to only 23% of the children diagnosed after this age. Changes in younger children were driven by improvements in social symptoms despite deterioration in restricted and repetitive behaviors. These findings reveal that autism spectrum disorder diagnosis before the age of 2.5 is associated with considerable improvement in social symptoms. We suggest that greater brain plasticity and behavioral flexibility enable younger children to benefit more from autism spectrum disorder interventions even in community settings with heterogeneous services. This motivates further prioritization of early autism spectrum disorder screening as recommended by American Academy of Pediatrics guidelines. Lay It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core autism spectrum disorder symptoms. In this study, we measured changes in core autism spectrum disorder symptoms over a 1–2-year period in 131 children diagnosed with autism spectrum disorder at 1.2–5 years of age, and treated in the community. The results revealed that children who were diagnosed before 2.5 years of age were three times more likely to exhibit considerable improvements in social autism spectrum disorder symptoms in comparison to children diagnosed at later ages. These results highlight the importance of early diagnosis and treatment of autism spectrum disorder even in community settings with heterogeneous services. In addition, these results motivate further prioritization of universal screening for autism spectrum disorder before 2.5 years of age.

In the United States, a black-to-white disparity in age-standardized breast cancer mortality rates emerged in the 1980s and has widened since then. To further explore this racial disparity, black-to-white rate ratios (RRs _BW ) for mortality, incidence, hazard of breast cancer death, and incidence-based mortality (IBM) were investigated using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program on 244 786 women who were diagnosed with breast cancer from January 1990 through December 2003 and followed through December 2004. A counterfactual approach was used to examine the expected IBM RRs _BW , assuming equal distributions for estrogen receptor (ER) expression, and/or equal hazard rates of breast cancer death, among black and white women. From 1990 through 2004, mortality RR _BW was greater than 1.0 and widened over time (age-standardized breast cancer mortality rates fell from 36 to 29 per 100 000 for blacks and from 30 to 22 per 100 000 for whites). In contrast, incidence RR _BW was generally less than 1.0. Absolute hazard rates of breast cancer death declined substantially for ER-positive tumors and modestly for ER-negative tumors but were persistently higher for blacks than whites. Equalizing the distributions of ER expression in blacks and whites decreased the IBM RR _BW slightly. Interestingly, the black-to-white disparity in IBM RR _BW was essentially eliminated when hazard rates of breast cancer death were matched within each ER category. The black-to-white disparity in age-standardized breast cancer mortality was largely driven by the higher hazard rates of breast cancer death among black women, diagnosed with the disease, irrespective of ER expression, and especially in the first few years following diagnosis. Greater emphasis should be placed on identifying the etiology of these excess hazards and developing therapeutic strategies to address them.