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1.
Biol Psychiatry ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33648717

RESUMO

BACKGROUND: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits. METHODS: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations. RESULTS: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior). CONCLUSIONS: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.

2.
J Affect Disord ; 282: 637-643, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33445086

RESUMO

OBJECTIVE: To evaluate the association between cardiometabolic markers and bipolar disorder (BD), examining the impact of sex and cardiometabolic medication use, from a large case-control biorepository of more than 1300 participants. PATIENTS AND METHODS: Recruited from July 2009 through September 2017, cardiometabolic markers were harvested from electronic health records (EHR) of participants (n=661) from the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder and Mayo Clinic Biobank age-sex-matched controls (n=706). Markers were compared between cases and controls using logistic regression, stratified by sex, adjusting for cardiometabolic medications and current smoking status. We studied the effect of psychotropics in case-only analyses. RESULTS: The mean age of the sample was 52.5 ± 11.6 years and 55% were female. BD patients had higher rates of smoking, but lower utilization of lipid-lowering medication compared with controls. After adjustment, BD was associated with obesity [Odds ratio (CI) 1.62 (1.22-2.15)], elevated systolic blood pressure (SBP) [2.18 (1.55-3.06)] and elevated triglycerides [1.58 (1.13-2.2)]. When stratified by sex, obesity [1.8 (1.23-2.66)] and systolic blood pressure [2.32 (1.46-3.7)] were associated with BD females compared to female controls; however, only systolic blood pressure [2.04 (1.23-3.42)] was associated with male bipolars compared to male controls. Psychotropics were marginally associated with mean BMI, abnormal triglycerides, and HbA1c. LIMITATIONS: EHR cross-sectional data CONCLUSION: To our knowledge, this is the largest case controlled study to date to explore the association between cardiometabolic markers and bipolar disorder adjusting for utilization of cardiometabolic medication. Identification of significant, non-laboratory based cardiometabolic markers that are associated with increased risk of major cardiovascular adverse events in patients with bipolar disorder, underscores, both the utility and importance of risk monitoring that can be easily done in community mental health centers.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33277321

RESUMO

BACKGROUND: Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner-Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45-74. We validate using prospective data from the Mayo Mammography Health Study (MMHS). METHODS: We derived the model in the Nurses' Health Study (NHS) based on: MD, 77SNP PRS and a questionnaire score (QS) (lifestyle and reproductive factors). 2799 invasive breast cancer cases were diagnosed from 1990-2000. MD (using Cumulus software) and PRS were assessed in a nested case-control study. We assess model performance using this case-control data set and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age <50, and 434 incident cases identified over 10 years of follow-up. RESULTS: In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: OR per SD =1.48 (95% CI 1.31 - 1.68), followed by PRS, OR per SD = 1.37 (95% CI 1.21 - 1.55) and QS, OR per SD = 1.25 (95% CI 1.11 - 1.41). In MMHS, the AUC adjusted for age was 0.595; for age+MD 0.636; for age+MD+QS 0.650; for age+MD+QS+PRS 0.687. CONCLUSIONS: A simplified assessment of QS, MD and PRS performs consistently to discriminate those at high 10-year breast cancer risk. IMPACT: This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinic setting to identify women who may benefit from chemopreventive intervention.

4.
Clin Sci (Lond) ; 134(20): 2729-2739, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33111948

RESUMO

Statistically significant findings are more likely to be published than non-significant or null findings, leaving scientists and healthcare personnel to make decisions based on distorted scientific evidence. Continuously expanding ´file drawers' of unpublished data from well-designed experiments waste resources creates problems for researchers, the scientific community and the public. There is limited awareness of the negative impact that publication bias and selective reporting have on the scientific literature. Alternative publication formats have recently been introduced that make it easier to publish research that is difficult to publish in traditional peer reviewed journals. These include micropublications, data repositories, data journals, preprints, publishing platforms, and journals focusing on null or neutral results. While these alternative formats have the potential to reduce publication bias, many scientists are unaware that these formats exist and don't know how to use them. Our open source file drawer data liberation effort (fiddle) tool (RRID:SCR_017327 available at: http://s-quest.bihealth.org/fiddle/) is a match-making Shiny app designed to help biomedical researchers to identify the most appropriate publication format for their data. Users can search for a publication format that meets their needs, compare and contrast different publication formats, and find links to publishing platforms. This tool will assist scientists in getting otherwise inaccessible, hidden data out of the file drawer into the scientific community and literature. We briefly highlight essential details that should be included to ensure reporting quality, which will allow others to use and benefit from research published in these new formats.

5.
Am J Reprod Immunol ; : e13343, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32905653

RESUMO

PROBLEM: Previous studies identified circulating CD14+ HLA-DRlo/- monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre- and post-frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy. METHOD OF STUDY: Incident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33+ CD11b+ HLA-DR-/low CD14+ CD15- monocytic cells, henceforth termed CD14+ HLA-DRlo/- monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14+ HLA-DRlo/- monocytic cell percentages and disease stage. Wilcoxon signed-rank tests evaluated changes in these monocytic cell levels pre- and post-chemotherapy in a patient subset (n = 70). RESULTS: Patients with elevated frequencies of circulating CD14+ HLA-DRlo/- monocytic cells at diagnosis were at 3.33-fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04-10.64), with a significant trend in increasing CD14+ HLA-DRlo/- monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post-chemotherapy among a subset of patients with advanced stage disease (P < .0001). CONCLUSION: These findings support the potential clinical relevance of CD14+ HLA-DRlo/- monocytic cells in EOC for prognosis and may indicate a non-invasive biomarker to measure disease progression.

6.
Cancer Prev Res (Phila) ; 13(11): 967-976, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32718942

RESUMO

Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5-4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46-0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31-0.97; P trend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33-0.80; P trend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31-0.89; P trend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose-response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.

7.
Int J Bipolar Disord ; 8(1): 23, 2020 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-32632502

RESUMO

BACKGROUND: Treatment in bipolar disorder (BD) is commonly applied as a multimodal therapy based on decision algorithms that lack an integrative understanding of molecular mechanisms or a biomarker associated clinical outcome measure. Pharmacogenetics/genomics study the individual genetic variation associated with drug response. This selective review of pharmacogenomics and pharmacogenomic testing (PGT) in BD will focus on candidate genes and genome wide association studies of pharmacokinetic drug metabolism and pharmacodynamic drug response/adverse event, and the potential role of decision support tools that incorporate multiple genotype/phenotype drug recommendations. MAIN BODY: We searched PubMed from January 2013 to May 2019, to identify studies reporting on BD and pharmacogenetics, pharmacogenomics and PGT. Studies were selected considering their contribution to the field. We summarize our findings in: targeted candidate genes of pharmacokinetic and pharmacodynamic pathways, genome-wide association studies and, PGT platforms, related to BD treatment. This field has grown from studies of metabolizing enzymes (i.e., pharmacokinetics) and drug transporters (i.e., pharmacodynamics), to untargeted investigations across the entire genome with the potential to merge genomic data with additional biological information. CONCLUSIONS: The complexity of BD genetics and, the heterogeneity in BD drug-related phenotypes, are important considerations for the design and interpretation of BD PGT. The clinical applicability of PGT in psychiatry is in its infancy and is far from reaching the robust impact it has in other medical disciplines. Nonetheless, promising findings are discovered with increasing frequency with remarkable relevance in neuroscience, pharmacology and biology.

8.
J Med Genet ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546565

RESUMO

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

9.
J Cancer Educ ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385740

RESUMO

Consent forms are an important educational tool that helps cancer patients decide on whether or not to enroll on a clinical trial, but wordiness potentially detracts from their educational value. This single-institution study examined word counts of consent forms for all phase I, II, and III solid tumor clinical trials between 2004 and 2010. Consent forms were categorized by trial funding source: (1) pharmaceutical company; (2) National Clinical Trials Network (NCTN); (3) R01- or other non-government grants; and (4) mixed (funding from multiple sources). Three hundred fifteen consent forms were studied; these included 106 (34%) pharmaceutical company; 145 (46%) NCTN; 44 (14%) R01 type; and 20 (6%) mixed. The overall median word count was 5129 words per consent form (interquartile range (IQR) range, 4226 to 6695). The median word counts per consent form (IQR) were 5648 (4814, 6803), 5243 (4139, 6932), 4365 (3806, 5124), and 4319 (3862, 5944), respectively, based on the above funding sources, showing that pharmaceutical company trial consent forms had the highest median word count. Of note, phase of trial was associated with consent form length (phase III were wordier), and consent forms manifested a consistent increase in wordiness over time. These observations underscore a timely need to find ways to limit the verbosity of consent forms, particularly in those from pharmaceutical company trials.

10.
Radiology ; 296(1): 24-31, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32396041

RESUMO

Background The associations of density measures from the publicly available Laboratory for Individualized Breast Radiodensity Assessment (LIBRA) software with breast cancer have primarily focused on estimates from the contralateral breast at the time of diagnosis. Purpose To evaluate LIBRA measures on mammograms obtained before breast cancer diagnosis and compare their performance to established density measures. Materials and Methods For this retrospective case-control study, full-field digital mammograms in for-processing (raw) and for-presentation (processed) formats were obtained (March 2008 to December 2011) in women who developed breast cancer an average of 2 years later and in age-matched control patients. LIBRA measures included absolute dense area and area percent density (PD) from both image formats. For comparison, dense area and PD were assessed by using the research software (Cumulus), and volumetric PD (VPD) and absolute dense volume were estimated with a commercially available software (Volpara). Density measures were compared by using Spearman correlation coefficients (r), and conditional logistic regression (odds ratios [ORs] and 95% confidence intervals [CIs]) was performed to examine the associations of density measures with breast cancer by adjusting for age and body mass index. Results Evaluated were 437 women diagnosed with breast cancer (median age, 62 years ± 17 [standard deviation]) and 1225 matched control patients (median age, 61 years ± 16). LIBRA PD showed strong correlations with Cumulus PD (r = 0.77-0.84) and Volpara VPD (r = 0.85-0.90) (P < .001 for both). For LIBRA, the strongest breast cancer association was observed for PD from processed images (OR, 1.3; 95% CI: 1.1, 1.5), although the PD association from raw images was not significantly different (OR, 1.2; 95% CI: 1.1, 1.4; P = .25). Slightly stronger breast cancer associations were seen for Cumulus PD (OR, 1.5; 95% CI: 1.3, 1.8; processed images; P = .01) and Volpara VPD (OR, 1.4; 95% CI: 1.2, 1.7; raw images; P = .004) compared with LIBRA measures. Conclusion Automated density measures provided by the Laboratory for Individualized Breast Radiodensity Assessment from raw and processed mammograms correlated with established area and volumetric density measures and showed comparable breast cancer associations. © RSNA, 2020 Online supplemental material is available for this article.

11.
J Affect Disord ; 266: 556-562, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056926

RESUMO

OBJECTIVE: Our aim was to investigate evening chronotype, a proxy marker of circadian system dysfunction, as a clinical subphenotype in bipolar disorder (BD). METHODS: In this cross-sectional study, 773 BD participants and 146 control subjects were evaluated using the Structured Clinical Interview for DSM-IV and a set of questionnaires. Chronotype was determined using item-5 from the reduced Morningness-Eveningness Questionnaire. Univariate analyses and regression models were used to compare evening and non-evening chronotype in BD and chronotype association with clinical variables. RESULTS: Overall, 205 (27%) of BD patients reported an evening chronotype. Evening chronotype was higher in a matched sub-sample of BD patients (n = 150) than in controls (24% and 5% respectively, OR=5.4, p<0.01). Compared to those with non-evening chronotypes, BD patients with an evening chronotype were younger, had an earlier age of onset of BD, and had more prior depressive and manic episodes, higher rates of rapid cycling, past suicide attempts, more comorbid anxiety and substance use disorders. Multivariate regression showed age, prior suicide attempts, and co-occurring substance use disorder were associated with evening chronotype (OR range of 0.97 to1.59). Hypertension, migraine, asthma, and obstructive sleep apnea were significantly associated with evening chronotype (OR range of 1.56 to 2.0). LIMITATION: Limitations include a cross-sectional study design that precludes establishing causality. Analyses did not control for medication use. Younger participant age may prevent evaluation of associations with late-life illnesses. CONCLUSIONS: Evening chronotype may be a discrete clinical subphenotype in BD and circadian dysfunction a shared pathophysiological mechanism between psychopathology and medical morbidity.

12.
Breast Cancer Res Treat ; 180(1): 55-61, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31933142

RESUMO

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.


Assuntos
Doenças Mamárias/etiologia , Doenças Mamárias/patologia , Epitélio/metabolismo , Epitélio/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Adulto , Biomarcadores , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Contagem de Células , Suscetibilidade a Doenças/imunologia , Feminino , Seguimentos , Humanos , Vigilância Imunológica , Pessoa de Meia-Idade , Fenótipo
13.
Biol Sex Differ ; 10(1): 57, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818333

RESUMO

BACKGROUND: Bipolar disorder (BD) affects both sexes, but important sex differences exist with respect to its symptoms and comorbidities. For example, rapid cycling (RC) is more prevalent in females, and alcohol use disorder (AUD) is more prevalent in males. We hypothesize that X chromosome variants may be associated with sex-specific characteristics of BD. Few studies have explored the role of the X chromosome in BD, which is complicated by X chromosome inactivation (XCI). This process achieves "dosage compensation" for many X chromosome genes by silencing one of the two copies in females, and most statistical methods either ignore that XCI occurs or falsely assume that one copy is inactivated at all loci. We introduce new statistical methods that do not make these assumptions. METHODS: We investigated this hypothesis in 1001 BD patients from the Genetic Association Information Network (GAIN) and 957 BD patients from the Mayo Clinic Bipolar Disorder Biobank. We examined the association of over 14,000 X chromosome single nucleotide polymorphisms (SNPs) with sex-associated BD traits using two statistical approaches that account for whether a SNP may be undergoing or escaping XCI. In the "XCI-informed approach," we fit a sex-adjusted logistic regression model assuming additive genetic effects where we coded the SNP either assuming one copy is expressed or two copies are expressed based on prior knowledge about which regions are inactivated. In the "XCI-robust approach," we fit a logistic regression model with sex, SNP, and SNP-sex interaction effects that is flexible to whether the region is inactivated or escaping XCI. RESULTS: Using the "XCI-informed approach," which considers only the main effect of SNP and does not allow the SNP effect to differ by sex, no significant associations were identified for any of the phenotypes. Using the "XCI-robust approach," intergenic SNP rs5932307 was associated with BD (P = 8.3 × 10-8), with a stronger effect in females (odds ratio in males (ORM) = 1.13, odds ratio in females for a change of two allele copies (ORW2) = 3.86). CONCLUSION: X chromosome association studies should employ methods which account for its unique biology. Future work is needed to validate the identified associations with BD, to formally assess the performance of both approaches under different true genetic architectures, and to apply these approaches to study sex differences in other conditions.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos X , Caracteres Sexuais , Adulto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único
14.
Breast Cancer Res ; 21(1): 118, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660981

RESUMO

BACKGROUND: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico , Mama/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Mamografia/métodos , Idoso , Automação , Estudos de Casos e Controles , Detecção Precoce de Câncer/instrumentação , Feminino , Humanos , Mamografia/instrumentação , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga Tumoral
15.
Circulation ; 140(18): 1506-1518, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31657957

RESUMO

Reports highlighting the problems with the standard practice of using bar graphs to show continuous data have prompted many journals to adopt new visualization policies. These policies encourage authors to avoid bar graphs and use graphics that show the data distribution; however, they provide little guidance on how to effectively display data. We conducted a systematic review of studies published in top peripheral vascular disease journals to determine what types of figures are used, and to assess the prevalence of suboptimal data visualization practices. Among papers with data figures, 47.7% of papers used bar graphs to present continuous data. This primer provides a detailed overview of strategies for addressing this issue by (1) outlining strategies for selecting the correct type of figure depending on the study design, sample size, and the type of variable; (2) examining techniques for making effective dot plots, box plots, and violin plots; and (3) illustrating how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. We also present solutions to other common problems identified in the systematic review. Resources include a list of free tools and templates that authors can use to create more informative figures and an online simulator that illustrates why summary statistics are meaningful only when there are enough data to summarize. Last, we consider steps that investigators can take to improve figures in the scientific literature.


Assuntos
Pesquisa Biomédica , Interpretação Estatística de Dados , Visualização de Dados , Projetos de Pesquisa/estatística & dados numéricos , Pesquisa Biomédica/métodos , Humanos , Tamanho da Amostra
16.
BMC Genomics ; 20(1): 689, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477010

RESUMO

BACKGROUND: Archived formalin fixed paraffin embedded (FFPE) samples are valuable clinical resources to examine clinically relevant morphology features and also to study genetic changes. However, DNA quality and quantity of FFPE samples are often sub-optimal, and resulting NGS-based genetics variant detections are prone to false positives. Evaluations of wet-lab and bioinformatics approaches are needed to optimize variant detection from FFPE samples. RESULTS: As a pilot study, we designed within-subject triplicate samples of DNA derived from paired FFPE and fresh frozen breast tissues to highlight FFPE-specific artifacts. For FFPE samples, we tested two FFPE DNA extraction methods to determine impact of wet-lab procedures on variant calling: QIAGEN QIAamp DNA Mini Kit ("QA"), and QIAGEN GeneRead DNA FFPE Kit ("QGR"). We also used negative-control (NA12891) and positive control samples (Horizon Discovery Reference Standard FFPE). All DNA sample libraries were prepared for NGS according to the QIAseq Human Breast Cancer Targeted DNA Panel protocol and sequenced on the HiSeq 4000. Variant calling and filtering were performed using QIAGEN Gene Globe Data Portal. Detailed variant concordance comparisons and mutational signature analysis were performed to investigate effects of FFPE samples compared to paired fresh frozen samples, along with different DNA extraction methods. In this study, we found that five times or more variants were called with FFPE samples, compared to their paired fresh-frozen tissue samples even after applying molecular barcoding error-correction and default bioinformatics filtering recommended by the vendor. We also found that QGR as an optimized FFPE-DNA extraction approach leads to much fewer discordant variants between paired fresh frozen and FFPE samples. Approximately 92% of the uniquely called FFPE variants were of low allelic frequency range (< 5%), and collectively shared a "C > T|G > A" mutational signature known to be representative of FFPE artifacts resulting from cytosine deamination. Based on control samples and FFPE-frozen replicates, we derived an effective filtering strategy with associated empirical false-discovery estimates. CONCLUSIONS: Through this study, we demonstrated feasibility of calling and filtering genetic variants from FFPE tissue samples using a combined strategy with molecular barcodes, optimized DNA extraction, and bioinformatics methods incorporating genomics context such as mutational signature and variant allelic frequency.


Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA/métodos , DNA de Neoplasias/isolamento & purificação , Mama/química , Feminino , Fixadores , Formaldeído , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inclusão em Parafina , Fixação de Tecidos
17.
Expert Rev Neurother ; 19(9): 867-879, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31269819

RESUMO

Introduction: Clinical and genetic study of psychiatric conditions has underscored the co-occurrence of complex phenotypes and the need to refine them. Bipolar Disorder (BD) and Binge Eating (BE) behavior are common psychiatric conditions that have high heritability and high co-occurrence, such that at least one quarter of BD patients have BE (BD + BE). Genetic studies of BD alone and of BE alone suggest complex polygenic risk models, with many genetic risk loci yet to be identified. Areas covered: We review studies of the epidemiology of BD+BE, its clinical features (cognitive traits, psychiatric comorbidity, and role of obesity), genomic studies (of BD, eating disorders (ED) defined by BE, and BD + BE), and therapeutic implications of BD + BE. Expert opinion: Subphenotyping of complex psychiatric disorders reduces heterogeneity and increases statistical power and effect size; thus, it enhances our capacity to find missing genetic (and other) risk factors. BD + BE has a severe clinical picture and genetic studies suggests a distinct genetic architecture. Differential therapeutic interventions may be needed for patients with BD + BE compared with BD patients without BE. Recognizing the BD + BE subphenotype is an example of moving towards more precise clinical and genetic entities.


Assuntos
Transtorno da Compulsão Alimentar , Transtorno Bipolar , Comorbidade , Transtorno da Compulsão Alimentar/epidemiologia , Transtorno da Compulsão Alimentar/genética , Transtorno da Compulsão Alimentar/fisiopatologia , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Humanos
18.
J Psychiatr Res ; 117: 45-54, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279243

RESUMO

Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation - an epigenetic mechanism both heritable and sensitive to the environment - may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.


Assuntos
Transtorno Bipolar/metabolismo , Metilação de DNA/fisiologia , Transtorno Depressivo Maior/metabolismo , Expressão Gênica/fisiologia , Genoma/fisiologia , Córtex Pré-Frontal/metabolismo , Lobo Temporal/metabolismo , Adulto , Idoso , Autopsia , Ilhas de CpG , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1324-1330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31186265

RESUMO

BACKGROUND: Mammographic breast density declines during menopause. We assessed changes in volumetric breast density across the menopausal transition and factors that influence these changes. METHODS: Women without a history of breast cancer, who had full field digital mammograms during both pre- and postmenopausal periods, at least 2 years apart, were sampled from four facilities within the San Francisco Mammography Registry from 2007 to 2013. Dense breast volume (DV) was assessed using Volpara on mammograms across the time period. Annualized change in DV from pre- to postmenopause was estimated using linear mixed models adjusted for covariates and per-woman random effects. Multiplicative interactions were evaluated between premenopausal risk factors and time to determine whether these covariates modified the annualized changes. RESULTS: Among the 2,586 eligible women, 1,802 had one premenopausal and one postmenopausal mammogram, 628 had an additional perimenopausal mammogram, and 156 had two perimenopausal mammograms. Women experienced an annualized decrease in DV [-2.2 cm3 (95% confidence interval, -2.7 to -1.7)] over the menopausal transition. Declines were greater among women with a premenopausal DV above the median (54 cm3) versus below (DV, -3.5 cm3 vs. -1.0 cm3; P < 0.0001). Other breast cancer risk factors, including race, body mass index, family history, alcohol, and postmenopausal hormone therapy, had no effect on change in DV over the menopausal transition. CONCLUSIONS: High premenopausal DV was a strong predictor of greater reductions in DV across the menopausal transition. IMPACT: We found that few factors other than premenopausal density influence changes in DV across the menopausal transition, limiting targeted prevention efforts.


Assuntos
Densidade da Mama , Mama/citologia , Pós-Menopausa/fisiologia , Pré-Menopausa/fisiologia , Índice de Massa Corporal , Mama/patologia , Feminino , Humanos , Estudos Longitudinais , Mamografia/métodos , Pessoa de Meia-Idade , Fatores de Risco , Saúde da Mulher
20.
Mod Pathol ; 32(12): 1834-1846, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31239549

RESUMO

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/análise , Queratina-7/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/análise , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica/diagnóstico , Sensibilidade e Especificidade
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