Correction For Multiple Analyses Research Articles

Influence of menstrual cycle and hormonal contraceptive use on MS symptom fluctuations: A pilot study.

In clinical practice, females with MS often report menstrually-related symptom fluctuations. Hypothetically, use of oral contraceptives (OCs) could reduce these fluctuations, particularly continuous OCs (11+ weeks of consistent exogenous hormones followed by 1 week placebo). To prospectively capture (1) whether neurologic and generalized symptoms vary with menstrual cycle phase and (2) whether type of contraception impacts symptom fluctuations. In this two-center pilot study, females with MS and a regular menstrual cycle prospectively tracked their menstrual cycles and completed symptom surveys for up to 6 months. Participants were categorized as 1) users of oral contraceptives, either a) cyclic or b) continuous, or 2) endogenously cycling, either c) hormonal intrauterine device (IUD) users or d) "none users" (e.g. no hormonal contraception; included condoms, copper IUD, tubal ligation, "fertility awareness methods"). There was no correction for multiple analyses. Altogether, 47/70 participants (67%) provided >4 weeks of data and were included in the analyses. Mean (SD) age was 35.0 (0.9) years, median (IQR) EDSS was 1.5 (1-2) and mean (SD) SymptoMScreen score was 10.4 (9.6). For endogenously cycling patients (IUD and none users), fatigue (MFIS) was lower in the perimenstrual period than in the luteal period (p<0.05). For continuous OC users, variability in symptoms was lower than for endogenously cycling females (MFIS: p<0.01; Daily Hassles, from Uplift & Hassles Survey: p<0.05) or cyclic OC users (MFIS: p<0.001). In this pilot study, symptom severity did not definitively fluctuate in relationship to the menstrual cycle in endogenously cycling participants. However, fatigue and daily hassles were less variable for participants using continuous OC than for cyclic OC users or no-OC users. Future confirmatory studies are warranted to further examine whether contraceptive choice can be leveraged to manage symptom fluctuation in cycling females with MS. Such studies could enroll larger cohorts over fewer cycles or employ incentivization and hormonal measurements to enhance participant retention and statistical power.

Randomisation inference beyond the sharp null: bounded null hypotheses and quantiles of individual treatment effects

Abstract Randomisation inference (RI) is typically interpreted as testing Fisher’s ‘sharp’ null hypothesis that all unit-level effects are exactly zero. This hypothesis is often criticised as restrictive and implausible, making its rejection scientifically uninteresting. We show, however, that many randomisation tests are also valid for a ‘bounded’ null hypothesis under which the unit-level effects are all non-positive (or all non-negative) but are otherwise heterogeneous. In addition to being more plausible a priori, bounded nulls are closely related to substantively important concepts such as monotonicity and Pareto efficiency. Reinterpreting RI in this way expands the range of inferences possible in this framework. We show that exact confidence intervals for the maximum (or minimum) unit-level effect can be obtained by inverting tests for a sequence of bounded nulls. We also generalise RI to cover inference for quantiles of the individual effect distribution as well as for the proportion of individual effects larger (or smaller) than a given threshold. The proposed confidence intervals for all effect quantiles are simultaneously valid, in the sense that no correction for multiple analyses is required. In sum, our reinterpretation and generalisation provide a broader justification for randomisation tests and a basis for exact non-parametric inference for effect quantiles.

Factor Structure of the Bar-On Emotional Quotient Inventory in Youth on the Autism Spectrum

Examination of emotional intelligence (EI) of autistic individuals has gained popularity. These efforts have included the BarOn Emotional Quotient Inventory, Youth Version (BarOn EQ-i YV); however, this measure was not standardized with this population and so its utility and the accuracy of its factor structure for this population is questionable. This study examined how well the factor structure as represented by a sample of autistic children and youth aligns with that described in the measure’s technical manual to clarify considerations for use. Results indicate poor metrics of model fit. Some factors were significantly correlated, though this was attenuated somewhat upon correction for multiple analyses. Two items from the interpersonal factor were negatively loaded, suggesting they should be subtracted from other items in that factor (in contrast to the standardized model). Implications for EI construct validity, understanding of EI in autism, and use of EI measures for this population are discussed.

How Is Body Composition and Nutrition Status Associated with Erythropoietin Response in Hemodialyzed Patients? A Single-Center Prospective Cohort Study.

Background: Anemia is the most common finding in patients with end-stage kidney disease undergoing renal replacement therapy. A certain percentage of patients does not respond adequately to erythropoietin (EPO) treatment, not being able to reach desirable hemoglobin levels even when treated with large-dose EPO and intravenous/oral iron. In our study, we wanted to further investigate how nutritional status is associated with erythropoietin responsiveness. To quantify EPO response, we used the Erythropoietin Resistance Index (ERI), which is defined as the weekly weight-adjusted dose of EPO divided by the hemoglobin level. Patients and methods: Seventy-eight patients undergoing hemodialysis were included. All of them were measured by a SECA mBCA body composition analyzer and evaluated by Kalantar-Zadeh’s MIS score. Routine biochemical tests were also taken into account. The Shapiro-Wilk test was used to study the distributions of quantitative variables, which were significantly different from normal (p < 0.05). We used nonparametric Mann-Whitney U-test to compare groups. Correlations were studied by means of Spearman’s rank correlation coefficient. Bonferroni correction for multiple testing was performed. To find independent determinants of ERI, we additionally performed multivariate analysis using the General Linear Model (GLM). Results: In terms of body composition, factors that are associated with high ERI are low BMI, low fat mass, low visceral fat volume, high total body water percentage, low phase angle and low fat-free mass. In addition to body composition parameters, total MIS score and IL-6 serum levels correlated positively with ERI value. IL-6 was an independent determinant of ERI value, based on multivariate analysis. After correction for multiple analysis, BMI and eGFR both remained significant factors associated with EPO response. Conclusions: It seems crucial to prevent inflammatory malnutrition as a part of a holistic approach to anemia treatment in dialysis patients.

Association of the Mediterranean diet with cognition in a Western population

AbstractBackgroundThe Mediterranean‐style diet (MD) is promoted as one of the healthiest dietary patterns and has been shown to reduce cognitive decline in some randomised controlled trials (RCTs). This pattern is plant‐based with a focus on vegetables, legumes, fish, and olive oil, with low intake of red meats and foods high in sugar and saturated fats. The Maintain Your Brain (MYB) study is an online multi‐domain RCT targeting modifiable risk factors for dementia, including diet. This study investigated cross‐sectional associations between adherence to a MD pattern and cognition.MethodsParticipants enrolled in MYB were recruited from the Sax Institute’s larger 45 and Up Study, and included those with all baseline MYB assessments (n=6236). Diet was assessed using the validated Mediterranean Diet and Culinary Index tool. This 50‐item tool assesses intake of nine desirable and four undesirable features of the MD diet and allows derivation of the Mediterranean Diet Adherence Screener (MEDAS). Computerised cognitive tests, administered through the MYB digital platform, were used to assess domains of executive function, complex attention, learning and memory and global cognition.ResultsParticipants were 46% male, with mean (SD) age 65.0 (5.8) years, BMI 26.6 (4.9) kg/m2 and well educated (46% with tertiary education). Higher MEDAS scores were associated with being female, younger, better educated and having a lower BMI (all p&lt;0.001). Overall participant adherence to a MD pattern was low; MEDAS score 6.1 (2.1)/14. After covariate adjustment and correction for multiple analyses in hierarchical linear regression models, better MEDAS scores were significantly associated with worse (lower) z‐scores for executive function (β ‐0.018, p=0.003). For every 1‐point higher MEDAS score, executive function z‐scores were 0.018 lower. This unexpected negative association was clinically very small. There were no significant associations with other cognitive domains.ConclusionAdherence to a MD was sub‐optimal in this well‐educated Australian sample. The one unexpected finding is likely not clinically meaningful given its size. Additionally, as this was a cross‐sectional study, reverse causality cannot be ruled out. Results from the main MYB RCT will provide data on MD acceptance and impact in a Western dietary environment.

Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept

BackgroundAlterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota.The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA.MethodsIn this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment.The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons.ResultsWe did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept.Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes.There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept.ConclusionsTreatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.

The implication of single-nucleotide polymorphisms in ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is an undesirable complication in the course of ovarian stimulation. This kind of stimulation is aimed at acquiring a sufficient number of high-quality oocytes in in vitro fertilization (IVF). Whereas the predisposition to OHSS could be impacted by genetic polymorphisms in susceptible genes, the present study has been jointly conducted with an Iranian cohort to scrutinize its relevant implication. Genomic DNA was extracted from blood samples of patients with a normal ovarian response (NOR) or with OHSS. Samples were analyzed to detect polymorphisms MTHFR rs1801131, MTHFR rs1801133, AMHR2 rs2002555, LHCGR rs2293275, PGR rs10895068, and SERPINE1 rs1799889. Variations of MTHFR, AMHR2, LHCGR, and PGR genes were significantly associated with the developing OHSS. After correction for multiple analysis, this difference was not evident for PGR genotypes. The polymorphic alleles of MTHFR (rs1801131 C-allele and rs1801133 T-allele), AMHR2 (rs2002555 G-allele), and LHCGR (rs2293275 G-allele) were significantly more prevalent among patients with OHSS compared to those in the NOR group. In contrast, the minor allele of PGR single-nucleotide polymorphism (SNP) (rs10895068, A-allele) was more prominent among patients with a NOR than those with OHSS. No significant difference was observed in genotypes or alleles of SERPINE1 rs1799889. The observations indicated that the minor alleles of MTHFR, AMHR2, and LHCGR genes could be considered an independent risk factor in susceptibility to OHSS. Nevertheless, polymorphic allele in the PGR rs10895068 SNP contributes to preventing OHSS occurrence. Therefore, it can be argued that these genes have a significant impact on OHSS.

Neuropathic pain in leprosy: symptom profile characterization and comparison with neuropathic pain of other etiologies.

Previous studies reported a high prevalence of neuropathic pain in leprosy, being especially present in "pharmacologically cured" patients. The presence of neuropathic pain in leprosy poses a supplementary burden in patient's quality of life, daily activities, and mood. The aim of this study was to assess whether neuropathic pain in leprosy has similar symptom profile as neuropathic pain of other etiologies and to retrospectively assess the efficacy of neuropathic pain medications regularly prescribed to leprosy. Leprosy and nonleprosy patients had their neuropathic pain characterized by the neuropathic pain symptom inventory (NPSI, ranges from 0 to 100, with 100 being the maximal neuropathic pain intensity) in a first visit. In a second visit, leprosy patients who had significant pain and received pharmacological treatment in the first evaluation were reassessed (NPSI) and had their pain profile and treatment response further characterized, including information on drugs prescribed for neuropathic pain and their respective pain relief. The pain characteristics based on NPSI did not significantly differ between leprosy and nonleprosy neuropathic pain patients in visit 1 after correction for multiple analyses, and cluster analyses confirmed these findings (ie, no discrimination between leprosy and nonleprosy groups; Pearson χ2 = 0.072, P = 0.788). The assessment of pain relief response and the drugs taken by each patient, linear regression analysis showed that amitriptyline, when effective, had the highest percentage of analgesic relief. Neuropathic pain in leprosy is as heterogeneous as neuropathic pain of other etiologies, further supporting the concept that neuropathic pain is a transetiological entity. Neuropathic pain in leprosy may respond to drugs usually used to control pain of neuropathic profile in general, and amitriptiline may constitute a potential candidate drug for future formal clinical trials aimed at controlling neuropathic pain in leprosy.

Inflammatory cytokines in major depressive disorder: A case-control study.

There is mixed evidence in the literature on the role of inflammation in major depressive disorder. Contradictory findings are attributed to lack of rigorous characterization of study subjects, to the presence of concomitant medical illnesses, to the small sample sizes, and to the limited number of cytokines tested. Subjects aged 18-70 years, diagnosed with major depressive disorder and presenting with chronic course of illness, as well as matched controls ( n = 236), were evaluated by trained raters and provided blood for cytokine measurements. Cytokine levels in EDTA plasma were measured with the MILLIPLEX Multi-Analyte Profiling Human Cytokine/Chemokine Assay employing Luminex technology. The Wilcoxon rank-sum test was used to compare cytokine levels between major depressive disorder subjects and healthy volunteers, before (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α) and after Bonferroni correction for multiple comparisons (IL-1α, IL-2, IL-3, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IFN-γ-inducible protein 10, Eotaxin, interferon-γ, monotype chemoattractant protein-1, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor and vascular endothelial growth factor). There were no significant differences in cytokine levels between major depressive disorder subjects and controls, both prior to and after correction for multiple analyses (significance set at p ⩽ 0.05 and p ⩽ 0.002, respectively). Our well-characterized examination of cytokine plasma levels did not support the association of major depressive disorder with systemic inflammation. The heterogeneity of major depressive disorder, as well as a potential sampling bias selecting for non-inflammatory depression, might have determined our findings discordant with the literature.

Sialyltransferase and Neuraminidase Levels/Ratios and Sialic Acid Levels in Peripheral Blood B Cells Correlate with Measures of Disease Activity in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Pilot Study.

ObjectiveWe attempted to determine whether the level of enzymes sialyltransferase (ST) and neuraminidase (Neu) and sialic acid (SIA) in patients with systemic lupus erythematosus (SLE) correlates with the SLE Disease Activity Index (SLEDAI) and in patients with rheumatoid arthritis (RA) correlates with the Disease Activity Score28 (DAS28).MethodsWe examined cell-surface levels of ST6Gal-1, Neu1, ST3Gal-1, Neu3, α-2,6-SIA, and α-2,3-SIA by using fluorescent anti-enzyme antibodies, fluorescent-conjugated Sambucus nigra lectin, and fluorescent-conjugated Maackia amurensis lectin on blood cells in SLE and RA patients and assessed correlations of these levels with SLEDAI and with DAS28. Areas under the curve (AUC) were calculated for different variables against SLEDAI.ResultsThe B-cell ST3Gal-1/Neu3 ratio positively correlated with SLEDAI scores (ρ = 0.409 and P = 0.002, statistically significant after Bonferroni’ correction for multiple analyses.). It was supported by the inverse correlation of B-cell Neu3 levels with SLEDAI scores (ρ = −0.264, P = 0.048). The B-cell ST3Gal-1/Neu3 ratio against SLEDAI yielded an AUC of 0.689, which was comparable to that of anti-dsDNA levels at 0.635. In contrast, both ST3Gal-1 and Neu3 levels of RA B cells (r = 0.376, P = 0.013; r = 0.425, P = 0.005, respectively) correlated positively with high disease-activity DAS28 scores.ConclusionB-cell ST3Gal-1/Neu3 ratios in SLE and B-cell ST3Gal-1 and Neu3 levels in RA with high disease-activity DAS28 scores correlated with disease activity measures and may be useful in monitoring disease activities.

Assisted reproduction and cancer risk: how useful are national databases?

In the ART group 2.0% of women developed a cancer over an average period of 7.3 years. In the non-ART group 2.9% of women developed a cancer over an average period of 16 years. Controlling for some basic confounders resulted in a hazard rate of 1.16 (95% confidence intervals (CI) 1.04–1.29) for the ART group versus the non-ART group. This suggests a 16% increase in cancer development rate over time in the women in the ART group. The large difference in follow-up time between the two groups is a little problematic; the hazard rate assumes the hazard or event rate in one group is a constant proportion of the hazard in the other group and there is no way to know whether this assumption holds. Stratified analysis per cancer group suggested that women in the ART group have a higher hazard rate for developing breast cancer— strangely enough not reported in the present study—and central nervous system (CNS) cancer (Reigstad et al. ,2 015a,b). This was even more pronounced in women that had undergone IVF. However, these excess risks were statistically non-significant after correction for multiple analyses. For all other cancers results seemed reassuring as no evidence for further differences in hazard rate were observed. Breast cancer is the most highly prevailing cancer in women in general but also in women during the fertile age period. Breast cancer accounts for .40% of all cancers in women below 40 years of age (Anders et al., 2009). In the Reigstad study database breast cancer accounted for almost 40% of all cancers. CNS cancer is rarer in these relatively young women. In the general population CNS cancers account for 4% of all cancers (Cancer Research UK—original data sources are available from http://www.cancerresearchuk.org). In the Reigstad study, CNS cancer occurred at a somewhat higher rate and accounted for 9% of cancers in the ART group and for 7% in the non-ART group. As the investigators suggest in their discussion, CNS cancer in women in the ART group might have been caused by fertility specific factors. Certain tumors of the pituitary gland are for instance known to be associated with infertility (Fourman and Fazeli, 2015). I am actually quite reassured in reading these data for two reasons. First, although the population data were very large and likely to be complete it was not collected for this analysis. As a result many wellestablished risk factors for cancer rates could not be accounted for as they are simply not known. Well-known risk factors for many cancers are BMI, cigarette smoking, use of alcohol, physical activity, socioeconomic status and ethnicity. A high BMI is also a risk factor for infertility. If obesity was more prevalent in the ART group, this risk factor for cancer could potentially explain (part) of the excess risk. However, imagine that some important adjustments for risk factors had been made and that an excess risk was still there. Would that prove that parous women after ART have a higher risk to develop cancer than women that did not undergo ART? Not necessarily as there is at least a second possible explanation for the observed higher incidence of cancer in women in the ART group—an earlier detection. Before undergoing ART, women undergo a fertility work-up. The family history, hormonal measurements and ultrasound scans can alert physicians at a much earlier stage. Though the investigators ruled out a large early detection effect by doing subanalyses excluding the first year of treatment, this earlier detection bias cannot completely be ruled out. Familiarity with the hospital and association with a successful ART might render women in the ART group more inclined to seek medical help when the first signs of their developing cancer appeared. Thus cancers may have been detected that would never have caused symptoms, or would have caused symptoms only many years later. Furthermore, women in the ART group that have been noticed in previous studies to have a relatively high social-economic status might also visit a specialist at an earlier stage. If true, the resulting earlier detection of the cancer would make a higher incidence rate of cancer in the ART group a logical finding. A longer follow-up time

Abstract P4-10-01: High dose omega-3 fatty acid supplementation modulates breast tissue biomarkers in post-menopausal women at high risk for development of breast cancer

Abstract Background: We conducted a pilot study of high dose omega-3 fatty acid (FA) supplementation in post-menopausal women to determine if risk biomarkers for breast cancer in benign breast tissue sampled by random peri-areolar aspiration (RPFNA) could be favorably modulated and to acquire preliminary data on possible mechanism of action. Methods: 35 post-menopausal women at increased risk for breast cancer were accrued to a trial of 6-month intervention with 4 g daily of omega-3-acid ethyl esters [1.86 g eicosapentaenoic acid (EPA), 1.5 g docosahexaenoic acid (DHA)]. Subjects had RPFNA performed pre- and post-intervention and specimens evaluated for cytomorphology and proliferation (Ki-67). FA composition was determined in plasma, red blood cells, and RPFNA specimens. Additional specimens were frozen for assessment of hormones, a panel of 11 adipokines and cytokines by Luminex, and gene expression. Results: 34 subjects completed study with specimens evaluable for change in biomarkers. The ratio of (EPA+DHA):Arachidonic Acid (AA) levels in erythrocyte phospholipid increased significantly by a median of 2.7-fold. Although there was a significant decrease in blood EPA+DHA between discontinuation at 6 months and 2 weeks later when RPFNA was performed, all ratios were above the baseline value (median 1.6-fold). There was favorable but not statistically significant modulation for cytologic evidence of atypia (53% at baseline to 41% at off-study). However, favorable modulation was exhibited for Masood score (medians of 15 to 14; p = 0.014), number of epithelial cells recovered (p = 0.019) and Ki-67 expression (medians of 1.7% to 0.75%, p = 0.036, despite 8 subjects having no Ki-67 expression at baseline). Luminex assay of serum indicated a statistically significant increase (p = 0.003) for adiponectin and decrease (p = 0.016) for TNF-alpha between baseline and off-study. For RPFNA specimens, there was a significant decrease (P = 0.001) in MCP-1 levels adjusted for protein content. By ELISA, serum high molecular weight adiponection increased (p = 0.046) and molar ratio of IGF-1:IGFBP3 decreased (p = 0.006). Note that all analyses were exploratory and without correction for multiple analyses. Conclusion: Favorable modulation of a variety of blood and tissue risk biomarkers, including cytomorphology and proliferation, along with good tolerability suggests that high dose omega-3 FA esters should be tested further in a placebo-controlled trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-10-01.

Adolescents at risk of psychosis have higher level of hopelessness than adolescents not at risk of psychosis

Background: Hopelessness has been a widely studied phenomenon in psychotic disorders. However, previous evidence of hopelessness in at-risk state of psychosis is lacking. The primary aim of the present study was to investigate associations between at-risk state of psychosis and the level of hopelessness, the secondary aim being to investigate, at item-level, hopelessness differences in hopelessness profile of adolescents at risk of psychosis. Methods: Hopelessness was assessed with the Beck Hopelessness Scale (BHS) and risk of psychosis with the PROD screen by an early detection team at the Helsinki University Central Hospital in a sample of 200 help-seeking adolescents between 11 and 22 years of age. Of them, 66 were classified as belonging to the at-risk of psychosis group and 134 to the not-at-risk of psychosis group. Results: The at-risk group scored higher in total sum scores of hopelessness than the not-at-risk group (9.15 vs. 6.63, P = 0.002). In an additional analysis of the BHS, the sub-item “I have great faith in the future” (P < 0.001) differed by risk status of psychosis after correction for multiple analysis. In a logistic regression analysis, BHS subfactor III (sum scores of items “I can't imagine what my life would be like in 10 years” and “I don't expect to get what I really want”) explained (P = 0.047) the at-risk status of psychosis after age, gender and other BHS subfactors had been adjusted for. Conclusions: Adolescents at risk of psychosis have higher hopelessness than other help-seekers. In light of a heightened possibility of suicidal behaviour, psychiatric care should pay attention to these findings.

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms

Because of the high costs associated with ascertainment of families most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. While microsatellite markers spaced every 10 centimorgans typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carry out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 SNPs. Of the ~1100 families, 972 were informative for further analyses and mean information content was 0.86 after pruning for LD. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with Bipolar II disorder (BPII) and 702 subjects with Recurrent Major Depression. Three affection status models were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus Recurrent Major Depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (Nonparametric Pairs Lod 3.4 for rs1046943 at 119 cM) and 9q21 (Nonparametric Pairs Lod 3.4 for rs722642 at 78 cM) using only BPI and SA, BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis we observed 59 parametric lods of 2 or greater, many of which are likely to be close to maximum possible scores. While some linkage findings may be false positives the results could help prioritize the search for rare variants using whole exome or genome sequencing.

Relationship of Clinic Medical Home Scores to Quality and Patient Experience

We tested the association between medical home characteristics and measures of technical quality and patient experience of care in the 21 clinics of a large medical group that had all achieved level III recognition from the National Committee for Quality Assurance. There was substantial variation among them in both scores on the recognition instrument and in clinic performance measures. However, the few statistically significant associations that were identified disappeared when correction for multiple analyses was applied. We conclude that among primary care clinics recognized as high-level medical homes, the instrument used to assess medical home characteristics cannot differentiate their quality.

Erratum

To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Season of birth and multiple sclerosis in Sweden

To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Diabetic Patients’ Medication Underuse, Illness Outcomes, and Beliefs About Antihyperglycemic and Antihypertensive Treatments

OBJECTIVE—The purpose of this study was to determine how patients’ beliefs about antihyperglycemic and antihypertensive medications relate to medication underuse and health status.RESEARCH DESIGN AND METHODS—In diabetic patients from an economically distressed region, we assessed perceived necessity and harmfulness for antihyperglycemic (n = 803) and antihypertensive (n = 573) medications, past year's medication underuse, A1C, systolic blood pressure (SBP), and diastolic blood pressure (DBP).RESULTS—After correction for multiple analyses, multivariate models indicated that perceived need for antihyperglycemic medication was associated with being younger, being prescribed insulin, and being prescribed multiple medications. Concern about antihyperglycemic medications was associated with being younger, African American, dissatisfied with information received about medication, and of low health literacy. For antihypertensives, perceived necessity was associated with having numerous medical comorbidities and being dissatisfied with medication information; concern was associated with being younger, dissatisfied with information received about medication, and of low health literacy. Up to one-half of patients underused at least one of the types of medication; many of these patients attributed this underuse to cost. For both types of medications, concern was significantly associated with both cost-related and non–cost-related underuse, and antihypertensive concern was associated with higher SBP and DBP.CONCLUSIONS—Even after adjustment for economic factors, patients who are younger, African American, or of low health literacy are especially concerned about medication harmfulness, which is in turn associated with medication underuse and higher blood pressure. To enhance adherence and outcomes, interventions should address patients’ underlying concerns about potential adverse treatment effects and focus on both cultural factors and health literacy.

Are there pre-existing neural, cognitive, or motoric markers for musical ability?

Adult musician’s brains show structural enlargements, but it is not known whether these are inborn or a consequence of long-term training. In addition, music training in childhood has been shown to have positive effects on visual–spatial and verbal outcomes. However, it is not known whether pre-existing advantages in these skills are found in children who choose to study a musical instrument nor is it known whether there are pre-existing associations between music and any of these outcome measures that could help explain the training effects. To answer these questions, we compared 5- to 7-year-olds beginning piano or string lessons ( n = 39) with 5- to 7-year-olds not beginning instrumental training ( n = 31). All children received a series of tests (visual–spatial, non-verbal reasoning, verbal, motor, and musical) and underwent magnetic resonance imaging. We found no pre-existing neural, cognitive, motor, or musical differences between groups and no correlations (after correction for multiple analyses) between music perceptual skills and any brain or visual–spatial measures. However, correlations were found between music perceptual skills and both non-verbal reasoning and phonemic awareness. Such pre-existing correlations suggest similarities in auditory and visual pattern recognition as well a sharing of the neural substrates for language and music processing, most likely due to innate abilities or implicit learning during early development. This baseline study lays the groundwork for an ongoing longitudinal study addressing the effects of intensive musical training on brain and cognitive development, and making it possible to look retroactively at the brain and cognitive development of those children who emerge showing exceptional musical talent.

Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene ( DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, −205-G/A, −7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder ( N=118) and controls ( N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the −205-A/G polymorphisms and disease, an excess of allele −7685-C was observed in patients ( p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium ( p<0.0001) and strongly associated with disease ( p<1×10 −5). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.