Comparing Parent and Child Self-report Measures of the State-Trait Anxiety Inventory in Children and Adolescents with a Chronic Health Condition.

Anxiety symptoms in children and adolescents with a chronic health condition have been estimated as high as 40% lifetime prevalence. Clinicians often rely on parent/caregiver information to supplement or substitute child self-report related to pediatric physical and mental health. We developed a caregiver proxy version (STAI-P) for the State-Trait Anxiety Inventory (STAI) State Anxiety Scale that was compared with a child self-report version in 201 parent-child dyads to evaluate its utility in measuring state anxiety in chronically ill youth. For patients aged 7-12, self-reports of state anxiety were moderately associated with parent distress and health provider-reported functional status, but negatively associated with parent STAI-P scores. For patients aged 13-17, self-reports of state anxiety were significantly associated with STAI-P scores, parent distress, and health provider-reported functional status. The STAI-P parent version may be a useful tool in identifying and addressing anxiety symptoms in youth living with a chronic health condition.

The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue.

OBJECTIVE: The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)-1 and COX-2 have been found to be increased in animal models of epilepsy. Knowing the cellular expression of COX-1 and COX-2 is the key to understanding their functional role; however, only 3 studies have investigated COX-2 expression in epilepsy in humans, and there are no reports on COX-1. In addition, previous studies have shown that certain inflammatory proteins up-regulate ATP binding cassette (ABC) transporter expression (thought to be responsible for drug resistance), but this relationship remains unclear in human tissue. This study sought to measure the expression of COX-1, COX-2, and translocator protein 18 kDa (TSPO, an inflammation biomarker acting as a positive control), as well as ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in brain tissue samples from people with drug-resistant MTLE. METHODS: Formalin-fixed paraffin-embedded surgical brain tissue was obtained from 33 patients with drug-resistant MTLE. Multiplex immunofluorescence was used to quantify the expression and distribution of COX-1, COX-2, TSPO, P-gp, and BCRP. RESULTS: COX-1 was expressed in microglia, and COX-2 and TSPO were expressed in microglia and neurons. BCRP density correlated significantly with TSPO density, suggesting a potential relationship between inflammatory markers and efflux transporters. SIGNIFICANCE: To the best of our knowledge, this study is the first to measure the cellular expression of COX-1, COX-2, and TSPO in microglia, astrocytes, and neurons in surgical brain tissue samples from patients with drug-resistant MTLE. Further research is needed to determine the effects of the COX inflammatory pathway in epilepsy, and how it relates to the expression of the ABC transporters P-gp and BCRP.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.

Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.

Genome-wide association of anthropometric traits in African- and African-derived populations.

Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations.

Phase II cancer clinical trials with heterogeneous patient populations.

The patient population for a Phase II trial often consists of multiple subgroups in terms of risk level. In this case, a popular design approach is to specify the response rate and the prevalence of each subgroup, to calculate the response rate of the whole population by the weighted average of the response rates across subgroups, and to choose a standard Phase II design such as Simon's optimal or minimax design to test the response rate for the whole population. In this case, although the prevalence of each subgroup is accurately specified, the observed prevalence among the accrued patients to the study may be quite different from the expected one because of the small sample size, which is typical in most Phase II trials. The fixed rejection value for a chosen standard Phase II design may be either too conservative (i.e., increasing the false rejection probability of the experimental therapy) if the trial accrues more high-risk patients than expected, or too anti-conservative (i.e., increasing the false acceptance probability of the experimental therapy) if the trial accrues more low-risk patients than expected. We can avoid such problems by adjusting the rejection values, depending on the observed prevalence from the trial. In this paper, we investigate the performance of the flexible designs compared with the standard design with fixed rejection values under various settings.

Interrogating local population structure for fine mapping in genome-wide association studies.

MOTIVATION: Adjustment for population structure is necessary to avoid bias in genetic association studies of susceptibility variants for complex diseases. Population structure may differ from one genomic region to another due to the variability of individual ancestry associated with migration, random genetic drift or natural selection. Current association methods for correcting population stratification usually involve adjustment of global ancestry between study subjects. RESULTS: We suggest interrogating local population structure for fine mapping to more accurately locate true casual genes by better adjusting the confounding effect due to local ancestry. By extensive simulations on genome-wide datasets, we show that adjusting global ancestry may lead to false positives when local population structure is an important confounding factor. In contrast, adjusting local ancestry can effectively prevent false positives due to local population structure and thus can improve fine mapping for disease gene localization. We applied the local and global adjustments to the analysis of datasets from three genome-wide association studies, including European Americans, African Americans and Nigerians. Both European Americans and African Americans demonstrate greater variability in local ancestry than Nigerians. Adjusting local ancestry successfully eliminated the known spurious association between SNPs in the LCT gene and height due to the population structure existed in European Americans. CONTACT: xiaofeng.zhu@case.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic correlates of the development of theta event related oscillations in adolescents and young adults.

The developmental trajectories of theta band (4-7Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. Associations between the theta EROs and genotypic variants of 4 KCNJ6 single nucleotide polymorphisms (SNPs) were found to vary with age, sex, scalp location, and task modality. Three of the four KCNJ6 SNPs studied here were found to be significantly associated with the same theta EROs in adults in a previous family genome wide association study. Since measures of the P3 response have been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of genetic effects on its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions.

A genome wide association study of fast beta EEG in families of European ancestry.

BACKGROUND: Differences in fast beta (20-28Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2). METHOD: In a sample of 1564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings. RESULTS: Three intronic variants located within DSE (dermatan sulfate epimerase) on 6q22 were associated with fast beta EEG at a genome wide significant level (p<5×10-8). The most significant SNP was rs2252790 (p<2.6×10-8; MAF=0.36; ß=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10-6) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10-4; ß=0.29). Previous studies have indicated that DSE is involved in a network of genes integral to membrane organization; gene-based tests indicated that several variants within this network (i.e., DSE, ZEB2, RND3, MCTP1, and CTBP2) were also associated with beta EEG (empirical p<0.05), and of these genes, ZEB2 and CTBP2 were associated with DSM-V Alcohol Use Disorder (AUD; empirical p<0.05).' DISCUSSION: In this sample of EA families enriched for AUDs, fast beta EEG is associated with variants within DSE on 6q22; the most significant SNP influences the mRNA expression of DSE and ROS1 in hippocampus and temporal cortex, brain regions important for beta EEG activity. Gene-based tests suggest evidence of association with related genes, ZEB2, RND3, MCTP1, CTBP2, and beta EEG. Converging data from GWAS, gene expression, and gene-networks presented in this study provide support for the role of genetic variants within DSE and related genes in neural hyperexcitability, and has highlighted two potential candidate genes for AUD and/or related neurological conditions: ZEB2 and CTBP2. However, results must be replicated in large, independent samples.

Family-based case-control study of MAOA and MAOB polymorphisms in Parkinson disease.

Monoamine oxidase (MAO) is an enzyme regulating metabolism of neurotransmitters such as dopamine. Two distinct forms of enzyme, encoded by genes MAOA and MAOB located on the X chromosome, have been considered as possible factors in the pathogenesis of Parkinson disease (PD). Previous association studies of PD and MAO genes reported inconsistent results. In this study, we used a large family-based data set to test associations between MAO genes and a risk of PD. The data set includes 298 female discordant sibpairs and 348 male discordant sibpairs. For this study, all subjects analyzed were white and families with known parkin mutations were removed. We analyzed 15 single nucleotide polymorphisms (SNPs) and a dinucleotide repeat marker in the MAO genes. Association was found with the intron 13 SNP of MAOB in the female subset (P = 0.02). No significant association was found in the male subset. Our results add to the evidence of involvement of MAOB in PD and suggest that the effect may be stronger in women.

Sample size computation for two-sample noninferiority log-rank test.

When an experimental therapy is less extensive, less toxic, or less expensive than a standard therapy, we may want to prove that the former is not worse than the latter through a noninferiority trial. In this article, we discuss a modification of the log-rank test for noninferiority trials with survival endpoint and propose a sample size formula that can be used in designing such trials. Performance of our sample size formula is investigated through simulations. Our formula is applied to design a real clinical trial.