Statistical Correction For Multiple Comparisons Research Articles

Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder: A post hoc analysis of a randomized controlled trial.

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems.

Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome

BackgroundPhelan McDermid syndrome (PMS) is a neurogenetic condition associated with a high prevalence of intellectual disability (ID) and autism spectrum disorder (ASD). This study provides a more comprehensive and quantitative profile of repetitive behaviors within the context of ID seen with the condition.MethodsIndividuals age 3–21 years with a confirmed PMS diagnosis participated in a multicenter observational study evaluating the phenotype and natural history of the disorder. We evaluated data collected from this study pertaining to repetitive behaviors from the Repetitive Behavior Scales-Revised (RBS-R).ResultsThere were n = 90 participants who were part of this analysis. Forty-seven percent (n = 42/90) were female, and the average age at baseline evaluation was 8.88 ± 4.72 years. The mean best estimate IQ of the cohort was 26.08 ± 17.67 (range = 3.4–88), with n = 8 with mild ID (or no ID), n = 20 with moderate ID, and n = 62 with severe-profound ID. The RBS-R total overall score was 16.46 ± 13.9 (compared to 33.14 ± 20.60 reported in previous studies of ASD) (Lam and Aman, 2007), and the total number of items endorsed was 10.40 ± 6.81 (range = 0–29). After statistical correction for multiple comparisons, IQ correlated with the RBS-R stereotypic behavior subscale score (rs = − 0.33, unadjusted p = 0.0014, adjusted p = 0.01) and RBS-R stereotypic behavior total number of endorsed items (rs = − 0.32, unadjusted p = 0.0019, adjusted p = 0.01). IQ did not correlate with any other RBS-R subscale scores.ConclusionsThe RBS-R total overall score in a PMS cohort appears milder compared to individuals with ASD characterized in previous studies. Stereotypic behavior in PMS may reflect cognitive functioning.

Relationships between neuropsychological impairments and functional outcome eight years after severe traumatic brain injury: Results from the PariS-TBI study

ABSTRACT Background/objectives The objective was to assess the relationships between neuropsychological impairments, functional outcome and life satisfaction in a longitudinal study of patients after a severe traumatic brain injury (TBI) (PariS-TBI study). Patients Out of 243 survivors, 86 were evaluated 8 years post-injury. They did not significantly differ from patients lost-to-follow up except for the latter being more frequently students or unemployed before the injury. Methods Outcome measures included the Glasgow Outcome Scale-Extended (GOS-E), a functional independence questionnaire, employment, mood, fatigue and satisfaction with life. Neuropsychological outcome was assessed by two ways: performance-based outcome measures, using neuropsychological tests and patient and relative-based measures. Results Neuropsychological measures were not significantly related to initial injury severity nor to gender, but were significantly related to age and education. After statistical correction for multiple comparisons, cognitive testing and cognitive questionnaires were significantly correlated with most outcome measures. By contrast, satisfaction with life was only related with patient-rated questionnaires. A regression analysis showed that the Trail-Making-Test-A was the best predictor of functional outcome, in addition to education duration. Conclusions Cognitive measures, particularly slowed information processing speed, were significant indicators of functional outcome at a long-term post-injury, beyond and above demographics or injury severity measures.

Juvenile myoclonic epilepsy shows increased posterior theta, and reduced sensorimotor beta resting connectivity

BackgroundWidespread structural and functional brain network changes have been shown in Juvenile Myoclonic Epilepsy (JME) despite normal clinical neuroimaging. We sought to better define these changes using magnetoencephalography (MEG) and source space connectivity analysis for optimal neurophysiological and anatomical localisation. MethodsWe consecutively recruited 26 patients with JME who underwent resting state MEG recording, along with 26 age-and-sex matched controls. Whole brain connectivity was determined through correlation of Automated Anatomical Labelling (AAL) atlas source space MEG timeseries in conventional frequency bands of interest delta (1−4 Hz), theta (4−8 Hz), alpha (8−13 Hz), beta (13−30 Hz) and gamma (40−60 Hz). We used a Linearly Constrained Minimum Variance (LCMV) beamformer to extract voxel wise time series of ‘virtual sensors’ for the desired frequency bands, followed by connectivity analysis using correlation between frequency- and node-specific power fluctuations, for the voxel maxima in each AAL atlas label, correcting for noise, potentially spurious connections and multiple comparisons. ResultsWe found increased connectivity in the theta band in posterior brain regions, surviving statistical correction for multiple comparisons (corrected p < 0.05), and decreased connectivity in the beta band in sensorimotor cortex, between right pre- and post- central gyrus (p < 0.05) in JME compared to controls. ConclusionsAltered resting-state MEG connectivity in JME comprised increased connectivity in posterior theta – the frequency band associated with long range connections affecting attention and arousal - and decreased beta-band sensorimotor connectivity. These findings likely relate to altered regulation of the sensorimotor network and seizure prone states in JME.

Regional changes in ∆FosB expression in rat brain following MDMA self-administration predict increased sensitivity to effects of locally infused MDMA.

Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague-Dawley rats. The effects of extensive 3,4-methylenedioxymethamphetamine (MDMA) self-administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug-naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor-activating effect of MDMA (200 μg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self-administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate-putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate-putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA-produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate-putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure.

Corrections for multiple comparisons in voxel-based lesion-symptom mapping

Voxel-based lesion-symptom mapping (VLSM) is an important method for basic and translational human neuroscience research. VLSM leverages modern neuroimaging analysis techniques to build on the classic approach of examining the relationship between location of brain damage and cognitive deficits. Testing an association between deficit severity and lesion status in each voxel involves very many individual tests and requires statistical correction for multiple comparisons. Several strategies have been adapted from analysis of functional neuroimaging data, though VLSM faces a more difficult trade-off between avoiding false positives and statistical power (missing true effects). We used simulated and real deficit scores from a sample of approximately 100 individuals with left hemisphere stroke to evaluate two such permutation-based approaches. Using permutation to set a minimum cluster size identified a region that systematically extended well beyond the true region, making it ill-suited to identifying brain-behavior relationships. In contrast, generalizing the standard permutation-based family-wise error correction approach provided a principled way to balance false positives and false negatives. Comparison with the widely-used parametric false discovery rate (FDR) correction showed that FDR produces anti-conservative results at smaller sample sizes (N = 30–60). An implementation of the continuous permutation-based FWER correction method described here is included in the lesymap package for lesion-symptom mapping (https://dorianps.github.io/LESYMAP/).

Trajectories of cortical surface area and cortical volume maturation in normal brain development.

This is a report of developmental trajectories of cortical surface area and cortical volume in the NIH MRI Study of Normal Brain Development. The quality-controlled sample included 384 individual typically-developing subjects with repeated scanning (1–3 per subject, total scans n=753) from 4.9 to 22.3 years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models, with statistical correction for multiple comparisons using random field theory. Analyses were performed with and without controlling for total brain volume. These data are provided for reference and comparison with other databases. Further discussion and interpretation on cortical developmental trajectories can be found in the associated Ducharme et al.׳s article “Trajectories of cortical thickness maturation in normal brain development – the importance of quality control procedures” (Ducharme et al., 2015) [1].

Comparison of Headbob Displays in Gray-Dewlapped and Red-Dewlapped Populations of Green Anoles (Anolis carolinensis)

Abstract: Green Anoles (Anolis carolinensis) are comprised of red-dewlapped (RD) forms that are found throughout the southeastern USA and a gray-dewlapped (GD) form that is restricted to southwest Florida. Prior research has shown that RD A. carolinensis produce headbob displays of three distinct types that differ primarily in their temporal patterns. Based on known morphological, physiological, and genetic differences between GD and RD populations, we hypothesized that these populations also would differ in headbob display structure. To test this hypothesis we quantified 440 displays from 39 males (24 GD and 15 RD) and assigned displays to type using numerical decision criteria. Although comparison of the same display types between GD and RD males revealed differences in the durations of several homologous display units (i.e., bobs or interbob pauses), only one unit differed following statistical correction for multiple comparisons. By taking into account all display variation in both populations simult...

Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder

BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. MethodsIn this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. ResultsWe found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Proteomic analysis allows for early detection of potential markers of metabolic impairment in very young obese children.

BackgroundEarly diagnosis of initial metabolic derangements in young obese children could influence their management; however, this impairment is frequently not overt, but subtle and undetectable by routinely used clinical assays. Our aim was to evaluate the ability of serum proteomic analysis to detect these incipient metabolic alterations in comparison to standard clinical methods and to identify new candidate biomarkers.MethodsA cross-sectional study of fasting serum samples from twenty-two prepubertal, Caucasian obese (OB; 9.22 ± 1.93 years; 3.43 ± 1.08 BMI-SDS) and twenty-one lean controls (C; 8.50 ± 1.98 years; -0.48 ± 0.81 BMI-SDS) and a prospective study of fasting serum samples from twenty prepubertal, Caucasian obese children (11 insulin resistant [IR]) before (4.77 ± 1.30 BMI-SDS) and after weight reduction (2.57 ± 1.29 BMI-SDS) by conservative treatment in a reference hospital (Pros-OB) was performed. Proteomic analysis (two-dimension-eletrophoresis + mass spectrometry analysis) of serum and comparative evaluation of the sensitivity of routinely used assays in the clinics to detect the observed differences in protein expression level, as well as their relationship with anthropometric features, insulin resistance indexes, lipid profile and adipokine levels were carried out.ResultsStudy of the intensity data from proteomic analysis showed a decrease of several isoforms of apolipoprotein-A1, apo-J/clusterin, vitamin D binding protein, transthyretin in OBvs. C, with some changes in these proteins being enhanced by IR and partially reversed after weight loss. Expression of low molecular weight isoforms of haptoglobin was increased in OB, enhanced in IR and again decreased after weight loss, being positively correlated with serum interleukin-6 and NAMPT/visfatin levels. After statistical correction for multiple comparisons, significance remained for a single isoform of low MW haptoglobin (OB vs. C and IR vs. non-IR) and Apo A1 (IR vs. non-IR). Assays routinely used in the clinical setting (ELISA/kinetic nephelometry), only partially confirmed the changes observed by proteomic analysis (ApoA1 and haptoglobin).ConclusionProteomic analysis can allow for the identification of potential new candidate biomarkers as a complement to routinely used assays to detect initial changes in serum markers of inflammation and lipid metabolism impairment in young obese children.

Functional MRI studies in non-CNS cancers

With increasing survival, cognitive problems after systemic treatment for non-CNS cancers are a growing concern. Functional magnetic resonance imaging (fMRI) is a noninvasive neuroimaging technique that has the potential to uncover the neural circuitry underlying cognitive problems after systemic treatment in cancer patients. Here, we provide an in depth review of the 14 fMRI studies that have been published to date on potential neurotoxic side effects of systemic treatment for non-CNS cancers. Cross-sectional studies in breast cancer survivors show a consistent pattern of hypoactivation in prefrontal and parietal brain regions during various executive functioning tasks 5 to 10years after completion of adjuvant chemotherapy that are sometimes associated with worse cognitive performance compared to cancer-specific or no-cancer controls. These findings suggest reduced neural functioning as a result of chemotherapy in brain regions that support cognitive functioning. With regard to episodic memory, hypoactivation at encoding is followed by hyperactivation at retrieval, suggestive of impairments in memory encoding that are compensated by neural hyperactivation to perform adequate memory retrieval. Prospective studies of executive functioning and episodic memory show a more complex picture of hypo- and hyperactivation that is possibly due to various counteracting mechanisms relatively shortly after chemotherapy. Two small studies in prostate cancer patients, finally, provide preliminary evidence for reduced activation in task-relevant brain regions after androgen deprivation therapy, suggestive of reduction of neural function. Statistical correction for multiple comparisons in the reviewed studies is typically quite lenient. We suggest that future studies should preferably include larger sample sizes to allow proper statistical correction for multiple comparisons and include comprehensive neurocognitive tests and multimodal MRI to facilitate the interpretation of the observed fMRI findings.

Profound changes in blood parameters during torpor in a South American marsupial

Seasonal torpor or hibernation is a phenomenon characterized by a physiological transition to dormancy (torpor) during challenging periods in terms of energy availability or metabolic load. Extensive physiological reprogramming and changes in gene-expression, immune function, oxygen transport and intermediate metabolism, occur during eutherian hibernation. Here we studied the seasonality of blood parameters, and during daily torpor, in a South American marsupial (Dromiciops gliroides). Seasonal trends in blood parameters showed an increase in hematological parameters during winter, and increases in total proteins, albumin and globulin during autumn. In contrast, torpor induced a drastic drop during most blood parameters. PCV dropped significantly 60%, as well as RBC (58%), hemoglobin concentration (58%), WBC (79%), including neutrophils (51%), eosinophils (84%) and lymphocytes (82%). Biochemical parameters also showed reductions: triglycerides (81%), proteins (32%), albumin (24%), globulins (38%), albumin (24%), creatinine (48%) and glucose (42%). Our results confirm some patterns observed in hibernating eutherians, such as leukopenia, probably caused by sequestration of white blood cells in organs. However, red blood cells and hemoglobin concentration also were reduced, which is to the best of our knowledge has not been reported for marsupials. The observed reduction in biochemical parameters suggests that marsupials, as in eutherians, change from carbohydrate-based to lipid-based metabolism during hibernation. However, the absence of increases in beta-hydroxybutyrate is puzzling. Finally, we found an increase (although non-significant after statistical correction for multiple comparisons) of creatine kinase which together with an increase in neutrophil/lymphocyte ratio could be indicative of muscle lysis and inflammation. These results indicate profound changes in standard physiological processes during torpor.

Anterior cingulate cortex and symptom severity in attention-deficit/hyperactivity disorder.

The cause of attention-deficit/hyperactivity disorder (ADHD) has been linked to abnormalities in prefrontal-striatal-cerebellar networks, but the brain-behavioral correlates are relatively equivocal. Children with ADHD and healthy controls underwent MRI and neuropsychological testing. Brain cortical thickness was analyzed for the bilateral rostral and caudal anterior cingulate cortex (ACC). Inhibitory control was assessed with the Stroop Inhibition test, and ADHD symptom severity was assessed with parent and teacher behavioral questionnaires. Brain-behavior relationships were calculated between cortical thickness and behavioral measures with regression models. Children with ADHD had significant cortical thinning in the right rostral ACC but nonsignificant thinning in right caudal, left caudal, or left rostral ACC compared with healthy control children after statistical correction for multiple comparisons. Further, right rostral ACC thickness predicted a significant amount of the variance in parent- and teacher-reported symptoms of ADHD. Exploratory analysis showed that cortical thickness was not related to psychostimulant medication history. Symptoms of ADHD may be related to reductions in cortical thickness in the right anterior attention network, a region implicated in behavioral error detection, impulsivity, and inhibitory control.

Circulating cytokines in sarcoidosis: Phenotype-specific alterations for fibrotic and non-fibrotic pulmonary disease

AimsSarcoidosis is a granulomatous disease of unknown etiology marked by tremendous clinical heterogeneity. Many patients enter remission with good long-term outcomes. Yet, chronic disease is not uncommon, and this important phenotype remains understudied. Identified alterations in local and circulating cytokines—specifically targeted for study, and often in the acute phase of disease—have informed our growing understanding of the immunopathogenesis of sarcoidosis. Our aim was to evaluate a broad panel of circulating cytokines in patients with chronic sarcoidosis. Among those with chronic disease, pulmonary fibrosis occurs in only a subset. To gain more insight into the determinants of the fibrotic response, we also determined if the phenotypes of fibrotic and non-fibrotic pulmonary sarcoidosis have distinct cytokine profiles. ResultsIn patients with sarcoidosis compared to controls, IL-5 was decreased, and IL-7 was increased. Both of these comparisons withstood rigorous statistical correction for multiple comparisons. GM-CSF met a nominal level of significance. We also detected an effect of phenotype, where IL-5 was significantly decreased in non-fibrotic compared to fibrotic pulmonary sarcoidosis, and compared to controls. Compared to controls, there was a trend towards a significant increase in IL-7 in fibrotic, but not in non-fibrotic pulmonary sarcoidosis. In contrast, compared to controls, there was a trend towards a significant increase in GM-CSF in non-fibrotic, but not in fibrotic pulmonary sarcoidosis. ConclusionsIn a comprehensive evaluation of circulating cytokines in sarcoidosis, we found IL-5, IL-7, and GM-CSF to be altered. These findings provide a window into the immunopathogenesis of sarcoidosis. IL-7 is a novel sarcoidosis cytokine and, as a master regulator of lymphocytes, is an attractive target for further studies. By observing an effect of phenotype upon cytokine patterns, we also identify specific immune alterations which may contribute to clinical heterogeneity.

Association of Human Leukocyte Antigens Class I and II Variants with Susceptibility to Pulmonary Tuberculosis in a Caucasian Population from Northern Spain

Background: Susceptibility to TB seems to be multifactorial, and the development of active disease is probably the result of complex interactions between the host and pathogen, influenced by environmental and genetic factors. The Human Leukocyte Antigen system or HLA seems to be one of these factors. Differences in the distribution of HLA alleles and haplotypes have been found worldwide with conflicting results among different populations and few data concerning Caucasian populations have been reported. Methods: Distribution of HLA class I and class II alleles was evaluated in 160 Spanish patients with pulmonary tuberculosis, all of them HIV negative, 109 latently infected individuals, and in 262 healthy individuals. All the subjects included in the study belonged to the same geographical area (Cantabria, northern Spain). Results: HLA-A*02 was found to be significantly more frequent in the latently infected group compared with the control group (34.86% versus 25.19%, p=0.009, OR 0.63 IC95% 0.45-0.89) and with patients with pulmonary tuberculosis (34.86% versus 25.79%, p=0.03, OR 0.65 IC95% 0.45-0.94). HLA-C*08 was found to be significantly more frequent in pulmonary tuberculosis patients compared with the control group (9.69% versus 5.34%, p=0.02, OR 1.91 IC95% 1.12-3.25). HLA-DRB1*04 was found to be significantly more frequent in pulmonary tuberculosis patients compared with the control group (17.19% versus 11.83%, p=0.037, OR 1.55 IC95% 1.04-2.29). Finally, HLA-DRB1*07 was found to be significantly more frequent in healthy and latently infected individuals compared with patients with pulmonary tuberculosis (19.66% & 21.10% versus 13.75%, p=0.036 & 0.034, OR 0.65 & 0.60 IC95% 0.44-0.96 & 0.38-0.94 respectively). The only haplotype which was significantly more frequent in pulmonary tuberculosis patients versus healthy individuals was the DRB1*04-DQA1*03-DQB1*03 extended three locus haplotype (p=0.04, OR 1.53 IC95% 1.03-2.72). All these differences disappeared after statistical correction for multiple comparisons. Conclusion: Although there were no significant differences in HLA alleles distribution among the three groups after statistical correction, there seems to be a slight trend of certain alleles in conferring protection against or susceptibility to pulmonary tuberculosis, at least in our population.

Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR)=1.55, 95% confidence interval (CI) 1.25-1.92, p=6.0×10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR=1.09, 95% CI 0.96-1.24, p=0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

A Quantitative Assessment of Tremor and Ataxia in FemaleFMR1Premutation Carriers Using CATSYS

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a relatively common cause of balance problems leading to gait disturbances in older males (40%) with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3), 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4), and 37 controls (mean age 56.53; SD 7.8). CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS.

Abnormal hippocampal shape in offenders with psychopathy

Posterior hippocampal volumes correlate negatively with the severity of psychopathy, but local morphological features are unknown. The aim of this study was to investigate hippocampal morphology in habitually violent offenders having psychopathy. Manual tracings of hippocampi from magnetic resonance images of 26 offenders (age: 32.5 +/- 8.4), with different degrees of psychopathy (12 high, 14 medium psychopathy based on the Psychopathy Checklist Revised), and 25 healthy controls (age: 34.6 +/- 10.8) were used for statistical modelling of local changes with a surface-based radial distance mapping method. Both offenders and controls had similar hippocampal volume and asymmetry ratios. Local analysis showed that the high psychopathy group had a significant depression along the longitudinal hippocampal axis, on both the dorsal and ventral aspects, when compared with the healthy controls and the medium psychopathy group. The opposite comparison revealed abnormal enlargement of the lateral borders in both the right and left hippocampi of both high and medium psychopathy groups versus controls, throughout CA1, CA2-3 and the subicular regions. These enlargement and reduction effects survived statistical correction for multiple comparisons in the main contrast (26 offenders vs. 25 controls) and in most subgroup comparisons. A statistical check excluded a possible confounding effect from amphetamine and polysubstance abuse. These results indicate that habitually violent offenders exhibit a specific abnormal hippocampal morphology, in the absence of total gray matter volume changes, that may relate to different autonomic modulation and abnormal fear-conditioning.

Orbitofrontal cortex volumes in medication naïve children with major depressive disorder: a magnetic resonance imaging study.

Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naïve children with MDD to determine whether abnormalities of OFC are present early in the illness course. Twenty seven medication naïve pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates. There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference. The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.