Enabling Factor Analysis on Thousand-Subject Neuroimaging Datasets

The scale of functional magnetic resonance image data is rapidly increasing as large multi-subject datasets are becoming widely available and high-resolution scanners are adopted. The inherent low-dimensionality of the information in this data has led neuroscientists to consider factor analysis methods to extract and analyze the underlying brain activity. In this work, we consider two recent multi-subject factor analysis methods: the Shared Response Model and Hierarchical Topographic Factor Analysis. We perform analytical, algorithmic, and code optimization to enable multi-node parallel implementations to scale. Single-node improvements result in 99x and 1812x speedups on these two methods, and enables the processing of larger datasets. Our distributed implementations show strong scaling of 3.3x and 5.5x respectively with 20 nodes on real datasets. We also demonstrate weak scaling on a synthetic dataset with 1024 subjects, on up to 1024 nodes and 32,768 cores

STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

Objective STEAP4 (six-transmembrane epithelial antigen of the prostate 4) is a metalloreductase that has been shown previously to protect cells from inflammatory damage. Genetic variants in STEAP4 have been associated with numerous metabolic disorders related to obesity, including putative defects in the acute insulin response to glucose in type 2 diabetes. Purpose We examined whether obesity and/or type 2 diabetes altered STEAP4 expression in human pancreatic islets. Methods Human islets were isolated from deceased donors at two medical centers and processed for quantitative polymerase chain reaction. Organ donors were selected by status as non-diabetic or having type 2 diabetes. Site 1 (Edmonton): N = 13 type 2 diabetes donors (7M, 6F), N = 20 non-diabetic donors (7M, 13F). Site 2 (Virginia): N = 6 type 2 diabetes donors (6F), N = 6 non-diabetic donors (3M, 3F). Results STEAP4 showed reduced islet expression with increasing body mass index among all donors (P < 0.10) and non-diabetic donors (P < 0.05) from Site 1; STEAP4 showed reduced islet expression among type 2 diabetes donors with increasing hemoglobin A1c. Islet STEAP4 expression was also marginally higher in female donors (P < 0.10). Among type 2 diabetes donors from Site 2, islet insulin expression was reduced, STEAP4 expression was increased, and white blood cell counts were increased compared to non-diabetic donors. Islets from non-diabetic donors that were exposed overnight to 5 ng/ml IL-1β displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling. Conclusions These findings suggest that increased STEAP4 mRNA expression is associated with inflammatory stimuli, whereas lower STEAP4 expression is associated with obesity in human islets. Given its putative protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage

The promoter from SlREO, a highly-expressed, root-specific Solanum lycopersicum gene, directs expression to cortex of mature roots

Root-specific promoters are valuable tools for targeting transgene expression, but many of those already described have limitations to their general applicability. We present the expression characteristics of SlREO, a novel gene isolated from tomato (Solanum lycopersicum L.). This gene was highly expressed in roots but had a very low level of expression in aerial plant organs. A 2.4-kb region representing the SlREO promoter sequence was cloned upstream of the uidA GUS reporter gene and shown to direct expression in the root cortex. In mature, glasshouse-grown plants this strict root specificity was maintained. Furthermore, promoter activity was unaffected by dehydration or wounding stress but was somewhat suppressed by exposure to NaCl, salicylic acid and jasmonic acid. The predicted protein sequence of SlREO contains a domain found in enzymes of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. The novel SlREO promoter has properties ideal for applications requiring strong and specific gene expression in the bulk of tomato root tissue growing in soil, and is also likely to be useful in other Solanaceous crop

A Smartphone-based Decision Support Tool Improves Test Performance Concerning Application of the Guidelines for Managing Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy

BACKGROUND: The American Society of Regional Anesthesia and Pain Medicine (ASRA) consensus statement on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy is the standard for evaluation and management of these patients. The authors hypothesized that an electronic decision support tool (eDST) would improve test performance compared with native physician behavior concerning the application of this guideline. METHODS: Anesthesiology trainees and faculty at 8 institutions participated in a prospective, randomized trial in which they completed a 20-question test involving clinical scenarios related to the ASRA guidelines. The eDST group completed the test using an iOS app programmed to contain decision logic and content of the ASRA guidelines. The control group completed the test by using any resource in addition to the app. A generalized linear mixed-effects model was used to examine the effect of the intervention. RESULTS: After obtaining institutional review board's approval and informed consent, 259 participants were enrolled and randomized (eDST = 122; control = 137). The mean score was 92.4 ± 6.6% in the eDST group and 68.0 ± 15.8% in the control group (P < 0.001). eDST use increased the odds of selecting correct answers (7.8; 95% CI, 5.7 to 10.7). Most control group participants (63%) used some cognitive aid during the test, and they scored higher than those who tested from memory alone (76 ± 15% vs. 57 ± 18%, P < 0.001). There was no difference in time to completion of the test (P = 0.15) and no effect of training level (P = 0.56). CONCLUSIONS: eDST use improved application of the ASRA guidelines compared with the native clinician behavior in a testing environment

Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors’ combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism–funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol

A South African mixed race lip/philtrum guide for diagnosis of fetal alcohol spectrum disorders

The adverse effects of maternal alcohol use during pregnancy represent a spectrum of growth restriction, facial dysmorphology, and neurocognitive challenges in the offspring. The continuum of diagnoses is referred to as fetal alcohol spectrum disorders (FASD). Short palpebral fissures, a smooth philtrum, and a thin vermilion border of the upper lip comprise the three cardinal facial features of FASD. Early attempts to define a smooth philtrum and thin vermilion border of the upper lip were subjective. Astley and colleagues introduced a 5-point Likert-scaled lip/philtrum guide based on Caucasian North American subjects as an objective tool for the evaluation of the facial dysmorphology in FASD. This Caucasian guide has been incorporated into all current diagnostic schemes for FASD. However, broad international clinical experience with FASD indicates racial and ethnic differences with respect to the facial morphology. Because of the substantial number of children with FASD in South Africa among the Cape Coloured (mixed race) population in the Western Cape Province, we developed a specific lip/philtrum guide for that population. The guide incorporates a 45-degree view of the philtrum that enables an enhanced 3-dimensional evaluation of philtral height not possible with a frontal view alone. The guide has proven to be a more specific and sensitive tool for evaluation of the facial dysmorphology of FASD in the Cape Coloured population than the use of the previous North American Caucasian guide and points to the utility of racial and ethnic-specific dysmorphology tools in the evaluation of children with suspected FASD

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Approaching the Prevalence of the Full Spectrum of Fetal Alcohol Spectrum Disorders in a South African Population-Based Study

The prevalence and characteristics of fetal alcohol spectrum disorders (FASD) were determined in this fourth study of first grade children in a South African community

Type 2 Diabetes Modifies the association of Cad Genomic Risk Variants With Subclinical atherosclerosis

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients