Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

Development and Psychometric Evaluation of a Caregiver Survey to Assess Family-Centered Care in the Emergency Department.

OBJECTIVE: To develop and evaluate the psychometric properties of a family caregiver-reported survey that assesses family-centeredness of care in the context of pediatric emergency department (ED) encounters. METHODS: We created a caregiver-reported scale, incorporated content expert feedback, and iteratively revised it based on cognitive interviews with caregivers. We then field tested the scale in a survey with caregivers. We dichotomized items using top-box scoring and obtained a summary score per respondent. Using a sample of 191 caregivers recruited from 9 EDs, we analyzed internal consistency reliability, dimensionality via item response theory modeling, and convergent validity with the ED Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. RESULTS: Feedback from the 9 experts led us to remove 4 items. We conducted 16 cognitive interviews and revised the survey in 4 rounds. An 11-item survey was field tested. Mean (standard deviation) respondent 11-item summary score was 77.2 (26.6). We removed 2 items given inconsistent response patterns, poor variability, and poor internal consistency, which increased coefficient alpha from 0.85 to 0.88 for the final scale. A multidimensional model fit the data best, but factor scores correlated strongly with summary scores, suggesting the latter are sufficient for quality improvement and future research. Regarding convergent validity, adjusted partial correlation between our scale's 9-item summary score and the ED CAHPS summary score was 0.75 (95% confidence interval 0.67-0.81). CONCLUSIONS: Psychometric analyses demonstrated strong item performance, reliability, and convergent validity for the 9-item scale. This survey can be used to assess family-centered care in the ED for research and quality improvement purposes.

Mitochondrial genome sequence analysis: a custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy.

BACKGROUND: Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform. RESULTS: An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control. CONCLUSIONS: Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughput and cost-efficient whole mitochondrial genome sequencing. This approach provides a viable alternative of potential utility for both clinical diagnostic and research applications to traditional Sanger and other emerging sequencing technologies for whole mitochondrial genome analysis.

Linking With External Covariates: Examining Accuracy by Anchor Type, Test Length, Ability Difference, and Sample Size.

Research has recently demonstrated the use of multiple anchor tests and external covariates to supplement or substitute for common anchor items when linking and equating with nonequivalent groups. This study examines the conditions under which external covariates improve linking and equating accuracy, with internal and external anchor tests of varying lengths and groups of differing abilities. Pseudo forms of a state science test were equated within a resampling study where sample size ranged from 1,000 to 10,000 examinees and anchor tests ranged in length from eight to 20 items, with reading and math scores included as covariates. Frequency estimation linking with an anchor test and external covariate was found to produce the most accurate results under the majority of conditions studied. Practical applications of linking with anchor tests and covariates are discussed.

Person-Fit as an Index of Inattentive Responding: A Comparison of Methods Using Polytomous Survey Data.

Self-report measures are vulnerable to response biases that can degrade the accuracy of conclusions drawn from results. In low-stakes measures, inattentive or careless responding can be especially problematic. A variety of a priori and post hoc methods exist for detecting these aberrant response patterns. Previous research indicates that nonparametric person-fit statistics tend to be the most accurate post hoc method for detecting inattentive responding on measures with dichotomous outcomes. This study investigated the accuracy and impact on model fit of parametric and nonparametric person-fit statistics in detecting inattentive responding with polytomous response scales. Receiver operating curve (ROC) analysis was used to determine the accuracy of each detection metric, and confirmatory factor analysis (CFA) fit indices were used to examine the impact of using person-fit statistics to identify inattentive respondents. ROC analysis showed the nonparametric H T statistic offered the most area under the curve when predicting a proxy for inattentive responding. The CFA fit indices showed the impact of using the person-fit statistics largely depends on the purpose (and cutoff) for using the person-fit statistics. Implications for using person-fit statistics to identify inattentive responders are discussed further.

Five-Minute Cognitive Test as A New Quick Screening of Cognitive Impairment in The Elderly.

This study aims to develop a new evaluation method for quickly and conveniently screening cognitive impairment in the elderly. The five-minute cognitive test (FCT) was designed to capture deficits in five domains of cognitive abilities, including episodic memory, language fluency, time orientation, visuospatial function, and executive function. Subsequently, FCT efficiencies in differentiating normally cognitive ability from cognitive impairment were explored and compared with that of the Mini-Mental Status Evaluation (MMSE). Equipercentile equating method was utilized to create a crosswalk between scores of the FCT and MMSE. Further, the association of scores of the FCT and MMSE with hippocampal volumes was investigated. There were 241 subjects aged 60 years or above enrolled in this study, including 107 adults with cognitive abilities in normal range, 107 patients with mild cognitive impairment (MCI), and 27 patients with mild Alzheimer disease (AD). The AUC of FCT for detection of cognitive impairment (MCI and mild AD) was 0.885 (95% CI 0.838 to 0.922). The sensitivity and specificity of FCT for the diagnosis of cognitive impairment were 80.6% and 84.11 %, respectively. FCT's diagnostic performance was superior to that of MMSE in the same cohort. Mean completion time of FCT was 339.9 ± 67.7 seconds (5-6 min). In addition, a conversion table between scores on the FCT and MMSE was created. Further, the FCT scores were positively correlated with hippocampal volumes. The FCT is a novel, reliable, and valid cognitive screening test for the detection of dementia at early stages.

Statistical equating with measures of oral reading fluency.

Recent research on curriculum-based measurement of oral reading fluency has revealed important issues in current passage development procedures, highlighting how dissimilar passages are problematic for monitoring student progress. The purpose of this paper is to describe statistical equating as an option for achieving equivalent scores across non-parallel reading passages. The psychometric and design properties of words-correct scores are examined, and the requirements of traditional equating methods are discussed. Simulated and empirical words-correct scores are used to demonstrate the steps in the equating process and the situations in which each method is most appropriate.

Examination of genetic variants influencing lipid traits in pediatric populations.

Previous large-scale genome-wide association studies in adult populations have implicated ∽100 loci in determining high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, or triglyceride levels. However, whether these loci also contribute to variations of lipid traits in pediatric populations remain unknown. Here we assayed a population of Philadelphia children by high-density single nucleotide polymorphism arrays, and performed association analysis on lipid traits ascertained from lipid measurements stored in electronic medical records. We examined previously reported lipid trait associations, and found that most of them show identical direction of association in our pediatric cohorts, including genome-wide significant association on cholesteryl ester transfer protein with HDL-C levels (rs3764261, P = 2.1 × 10(-8)) and other significant associations on oxysterol-binding protein-like protein 7, low-density lipoprotein receptor-related protein 4 and low-density lipoprotein receptor-related protein 1. Additionally, we identified suggestive association on low-density lipoprotein receptor-related protein 1B with HDL-C levels (rs17736712, P = 2.1 × 10(-7)), but this signal is not supported by previous meta-analysis on adult cohorts. Finally, we examined rare copy number variants and identified deletions encompassing tetratricopeptide repeat domain 39B in two children with extreme lipid measures. Our results highlight the commonalities and differences of genetic components in determining lipid traits in pediatric versus adult populations. Furthermore, our study demonstrates the unique utility of automated information retrieval from electronic medical records in facilitating the identification of genotype-phenotype associations.

Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer.

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 x 10(-8) in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29-4.13; OR = 3.07, 95% CI = 2.29-4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 x 10(-6) in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14-1.64; OR = 1.39, 95% CI = 1.16-1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.