Miracle-dz/UniFAR-FTUs huggingface dataset:
Validation of a method for noninvasive prenatal testing for fetal aneuploidies risk and considerations for its introduction in the Public Health System

Abstract Objective: The aim of this study was to validate noninvasive prenatal testing (NIPT) for fetal aneuploidies by whole-genome massively parallel sequencing (MPS). Methods: MPS was performed on cell-free DNA (cfDNA) isolated from maternal plasma in two groups: a first set of 186 euploid samples and a second set of 195 samples enriched of aneuploid cases (n = 69); digital PCR for fetal fraction (FF) assessment was performed on 178/381 samples. Cases with <10 × 106 reads (n = 54) were excluded for downstream data analysis. Follow-up data (invasive testing results or neonatal information) were available for all samples. Performances in terms of specificity/sensitivity and Z-score distributions were evaluated. Results: All positive samples for trisomy 21 (T21) (n = 43), trisomy 18 (T18) (n = 6) and trisomy 13 (T13) (n = 7) were correctly identified (sensitivity: 99.9%); 5 false positive results were reported: 3 for T21 (specificity = 98.9%) and 2 for T13 (specificity = 99.4%). Besides FF, total cfDNA concentration seems another important parameter for MPS, since it influences the number of reads. Conclusions: The overall test accuracy allowed us introducing NIPT for T21, T18 and T13 as a clinical service for pregnant women after 10 + 4 weeks of gestation. Sex chromosome aneuploidy assessment needs further validation due to the limited number of aneuploid cases in this study.
The link between allergy and Menière's disease

Purpose of reviewTo examine evidence supporting the association of allergy and Menière's disease. Recent findingsAnimal studies have shown evidence that a provoked systemic immune challenge can result in an allergic reaction within the inner ear, whereas premedication with leukotriene antagonists can prevent the development of endolymphatic hydrops. In human subjects, further data support a heightened allergic response in patients with Menière's disease, whereas pharmacological treatments that target histamine receptors help to control vertiginous symptoms. However, the relationship of migraine with a history of allergy and Menière's disease may confound this association. SummaryAlthough the evidence of a causal association between allergy and Menière's disease is inconclusive, the inclusion of allergy control as part of the treatment plan for Menière's disease is low risk to the patient and should be considered for patients with indications that include history of seasonal or food allergy, childhood or family history of allergy, bilateral Menière's symptoms, or a development of symptoms within a short time after exposure of food or inhaled allergen.
A place for innovation and rigorous surgical research in evidence-based medicine.

DOI:10.1097/MOO.0000000000000075 It is my pleasure to introduce this issue of Current Opinion in Otolaryngology-Head and Neck Surgery. One of the most frequent comments from an audience of surgeons after an evidence-based medicine (EBM) lecture is a criticism that EBM leads to more narrowed treatment options, less emphasis on individualized care, and an algorithmic approach to patients. Others complain about the stifling of innovative treatment options and emphasis on ‘levels of evidence. ’ In a 1996 article, Sackett commented, ‘Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of EBM means integrating individual clinical expertise with the best available external clinical evidence from systematic research’ [1]. It is a failed response for supporters of EBMguided practice to suggest more randomized controlled trials (RCTs) in surgery, for these are not likely plausible. Unlike standardized dosages of medications, surgery is dispensed with additional variables, many of which are systems-based, regionally specific, and dependent on preoperative preparation, anesthesia, postoperative care, and socioeconomic factors. Although the surgeon’s knife may perform flawlessly, the system can fail. My suggestion to these naysayers is to consider the value of improving the overall systems that play into our surgical outcomes. Instead of focusing on assessing each surgical decision in terms of the ‘pyramid of evidence,’ focus on the translation of the principles of EBM (‘Ask the clinical question, Acquire the evidence, Appraise the evidence, Apply to patient, and Assess the effectiveness’) in the context of the entire care delivery process. Perhaps the cleft lip rhinoplasty surgical incision should not be studied in a RCT between two major centers, but the outcomes of those centers can be obtained for internal quality assurance. We cannot effectively compare two treatment options without measuring the outcomes in a reliable, standardized fashion between surgeons, institutions, regions, and countries. These data standards are necessary to propel the field forward and are incredibly timeconsuming and difficult.
Panorama nacional do ensino da psiquiatria nas escolas médicas brasileiras

OBJECTIVE: To determine the profile of psychiatric teaching in Brazilian medical schools, with a focus on the number of professors involved and their respective degrees, the number of disciplines devoted to psychiatry and the predominant approach (psychodynamic/clinical/other) adopted, the didactic materials employed and the teaching and learning facilities available. METHODS: The study was based on the collection of data via application of questionnaires at all medical schools registered with the Brazilian Association of Medical Education (Associacao Brasileira de Educacao Medica). RESULTS: Of the 119 Brazilian schools contacted, 85 (71%) returned the questionnaires. The number of professors graduated in psychiatry at each school varied from 1 to 5 (75.3%); of these, 1 to 2 (43.4%) had a PhD degree, 1 to 2 (45.8%) a master's degree, and 1 to 2 (57.3%) were specialists. The findings revealed that 41.2% of the schools offered two disciplines of psychiatry, with a predominantly psychodynamic/clinical approach (61.2%). At 52.9% of the schools, teaching of psychiatric topics was not restricted to the specific disciplines; 64.7% of the disciplines offered hands-on training in general clinical settings. Mean number of credit hours of psychiatric teaching along the medical program was 61-90 (26.2%), and 88.9% of the programs used books as the main choice for didactic purposes. At 83.3% of the medical schools, psychiatric teaching is graded by students at the end of each discipline. CONCLUSION: The present findings revealed an important heterogeneity in the geographic regions assessed, affecting at least 71% of the schools. New studies are warranted to advance the preliminary findings herein reported.
On multiple‐testing correction in genome‐wide association studies

The interpretation of the results of large association studies encompassing much or all of the human genome faces the fundamental statistical problem that a correspondingly large number of single nucleotide polymorphisms markers will be spuriously flagged as significant. A common method of dealing with these false positives is to raise the significance level for the individual tests for association of each marker. Any such adjustment for multiple testing is ultimately based on a more or less precise estimate for the actual overall type I error probability. We estimate this probability for association tests for correlated markers and show that it depends in a nonlinear way on the significance level for the individual tests. This dependence of the effective number of tests is not taken into account by existing multiple‐testing corrections, leading to widely overestimated results. We demonstrate a simple correction for multiple testing, which can easily be calculated from the pairwise correlation and gives far more realistic estimates for the effective number of tests than previous formulae. The calculation is considerably faster than with other methods and hence applicable on a genome‐wide scale. The efficacy of our method is shown on a constructed example with highly correlated markers as well as on real data sets, including a full genome scan where a conservative estimate only 8% above the permutation estimate is obtained in about 1% of computation time. As the calculation is based on pairwise correlations between markers, it can be performed at the stage of study design using public databases. Genet. Epidemiol. 2008. 2008 Wiley‐Liss, Inc.
Identification of gene‐gene interactions in the presence of missing data using the multifactor dimensionality reduction method

Gene‐gene interaction is believed to play an important role in understanding complex traits. Multifactor dimensionality reduction (MDR) was proposed by Ritchie et al. [2001. Am J Hum Genet 69:138–147] to identify multiple loci that simultaneously affect disease susceptibility. Although the MDR method has been widely used to detect gene‐gene interactions, few studies have been reported on MDR analysis when there are missing data. Currently, there are four approaches available in MDR analysis to handle missing data. The first approach uses only complete observations that have no missing data, which can cause a severe loss of data. The second approach is to treat missing values as an additional genotype category, but interpretation of the results may then be not clear and the conclusions may be misleading. Furthermore, it performs poorly when the missing rates are unbalanced between the case and control groups. The third approach is a simple imputation method that imputes missing genotypes as the most frequent genotype, which may also produce biased results. The fourth approach, Available, uses all data available for the given loci to increase power. In any real data analysis, it is not clear which MDR approach one should use when there are missing data. In this article, we consider a new EM Impute approach to handle missing data more appropriately. Through simulation studies, we compared the performance of the proposed EM Impute approach with the current approaches. Our results showed that Available and EM Impute approaches perform better than the three other current approaches in terms of power and precision. Genet. Epidemiol. 33:646–656, 2009. © 2009 Wiley‐Liss, Inc.
Bayesian mixture modeling of gene‐environment and gene‐gene interactions

With the advent of rapid and relatively cheap genotyping technologies there is now the opportunity to attempt to identify gene‐environment and gene‐gene interactions when the number of genes and environmental factors is potentially large. Unfortunately the dimensionality of the parameter space leads to a computational explosion in the number of possible interactions that may be investigated. The full model that includes all interactions and main effects can be unstable, with wide confidence intervals arising from the large number of estimated parameters. We describe a hierarchical mixture model that allows all interactions to be investigated simultaneously, but assumes the effects come from a mixture prior with two components, one that reflects small null effects and the second for epidemiologically significant effects. Effects from the former are effectively set to zero, hence increasing the power for the detection of real signals. The prior framework is very flexible, which allows substantive information to be incorporated into the analysis. We illustrate the methods first using simulation, and then on data from a case‐control study of lung cancer in Central and Eastern Europe. Genet. Epidemiol. 34:16–25, 2010. © 2009 Wiley‐Liss, Inc.
Awaiting blood pressure stabilization in ambulatory pregnant women: is 5 minutes sufficient?

Abstract Objective: Current recommendations for timing of blood pressure measurement in ambulatory pregnant women vary and are based on studies in the nonpregnant population. The objective of this study was to determine if there is a difference in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between minute-5 and minute-10. Methods: A prospective study was conducted at our prenatal care clinics. Participants had their blood pressure measured upon sitting and every 5 minutes for 15 minutes. Initial SBP and DBP were compared to measurements at each time point. Additionally, the SBP and DBP at minute-5 were compared to minute-10. All statistical tests were two-sided. Results: Data from 400 patients were analyzed. Of these, 34.0% were in the first, 30.7% were in the second trimester, and 35.2% were in the third trimester. In each trimester, there was a significant difference in the SBP and DBP at minute-5 compared to minute-0. At minute-10 compared to minute-5, there was no further drop for all trimesters, except for a small drop in DBP in the second trimester (−1.3 ± 6.0, p = 0.012). Conclusion: In an ambulatory setting, 5 minutes after sitting appears to be an appropriate time point to measure blood pressure in pregnancy.
Robust and Powerful Tests for Rare Variants Using Fisher's Method to Combine Evidence of Association From Two or More Complementary Tests

Many association tests have been proposed for rare variants, but the choice of a powerful test is uncertain when there is limited information on the underlying genetic model. Proposed methods use either linear statistics, which are powerful when most variants are causal and have the same direction of effect, or quadratic statistics, which are more powerful in other scenarios. To achieve robustness, it is natural to combine the evidence of association from two or more complementary tests. To this end, we consider the minimum‐p and Fisher's methods of combining P‐values from linear and quadratic statistics. Extensive simulation studies show that both methods are robust across models with varying proportions of causal, deleterious, and protective rare variants, allele frequencies, and effect sizes. When the majority (>75%) of the causal effects are in the same direction (deleterious or protective), Fisher's method consistently outperforms the minimum‐p and the individual linear and quadratic tests, as well as the optimal sequence kernel association test, SKAT‐O. When the individual test has moderate power, Fisher's test has improved power for 90% of the ∼5000 models considered, with >20% relative efficiency gain for 40% of the models. The maximum absolute power loss is 8% for the remaining 10% of the models. An application to the GAW17 quantitative trait Q2 data based on sequence data of the 1000 Genomes Project shows that, compared with linear and quadratic tests, Fisher's test has comparable power for all 13 functional genes and provides the best power for more than half of them.
Apresentação anatomopatológica das vasculites pulmonares

The pathological manifestations of pulmonary vasculitis include an inflammatory process in the pulmonary vessel walls, which is often accompanied by granulomas, giant cells, eosinophils, necrosis or pulmonary hemorrhage. Knowledge of these presentations, as well as of the type of vessels affected and of immunofluorescence reactions, can aid in making the differential diagnosis among the various forms of vasculitis.
Sentinel node biopsy for early oral carcinoma

Purpose of reviewSentinel node biopsy (SNB) in oral squamous cell carcinomas (OSCCs) has been under investigation since more than a decade. Numerous published studies and recent important scientific data support its role as an alternative standard of care apart from elective neck dissection. Recent findingsDuring the past 2 years, a large-scale multicentric validation trial and long-term follow-ups of major observational trials have demonstrated the accuracy and oncological safety and efficacy of SNB to stage a cN0 early stage OSCC. Histologic and molecular parameters of the primary tumors possibly predicting occult disease in the neck have been evaluated, but SNB with the use of step-serial sectioning and immunohistochemistry remains the most accurate staging method. SNB has been shown to be clearly superior to elective neck dissection with regard to complications and morbidity. The modern technique of quantitative real-time reverse transcriptase–polymerase chain reaction has been successfully used for the rapid intraoperative assessment of the sentinel nodes, allowing a one-stage procedure in all patients. The procedure of SNB is currently expanding to other areas like the supraglottic larynx and the previously treated neck. SummarySNB in OSCC is a minimally invasive and highly reliable staging method of the cN0 neck and has become the standard of care in many centers throughout the world. Recent developments have led to a wider clinical application and improved acceptance.
Integrative gene set enrichment analysis utilizing isoform‐specific expression

Gene set enrichment analysis (GSEA) aims at identifying essential pathways, or more generally, sets of biologically related genes that are involved in complex human diseases. In the past, many studies have shown that GSEA is a very useful bioinformatics tool that plays critical roles in the innovation of disease prevention and intervention strategies. Despite its tremendous success, it is striking that conclusions of GSEA drawn from isolated studies are often sparse, and different studies may lead to inconsistent and sometimes contradictory results. Further, in the wake of next generation sequencing technologies, it has been made possible to measure genome‐wide isoform‐specific expression levels, calling for innovations that can utilize the unprecedented resolution. Currently, enormous amounts of data have been created from various RNA‐seq experiments. All these give rise to a pressing need for developing integrative methods that allow for explicit utilization of isoform‐specific expression, to combine multiple enrichment studies, in order to enhance the power, reproducibility, and interpretability of the analysis. We develop and evaluate integrative GSEA methods, based on two‐stage procedures, which, for the first time, allow statistically efficient use of isoform‐specific expression from multiple RNA‐seq experiments. Through simulation and real data analysis, we show that our methods can greatly improve the performance in identifying essential gene sets compared to existing methods that can only use gene‐level expression.
Iterative hard thresholding for model selection in genome‐wide association studies

A genome‐wide association study (GWAS) correlates marker and trait variation in a study sample. Each subject is genotyped at a multitude of SNPs (single nucleotide polymorphisms) spanning the genome. Here, we assume that subjects are randomly collected unrelateds and that trait values are normally distributed or can be transformed to normality. Over the past decade, geneticists have been remarkably successful in applying GWAS analysis to hundreds of traits. The massive amount of data produced in these studies present unique computational challenges. Penalized regression with the ℓ1 penalty (LASSO) or minimax concave penalty (MCP) penalties is capable of selecting a handful of associated SNPs from millions of potential SNPs. Unfortunately, model selection can be corrupted by false positives and false negatives, obscuring the genetic underpinning of a trait. Here, we compare LASSO and MCP penalized regression to iterative hard thresholding (IHT). On GWAS regression data, IHT is better at model selection and comparable in speed to both methods of penalized regression. This conclusion holds for both simulated and real GWAS data. IHT fosters parallelization and scales well in problems with large numbers of causal markers. Our parallel implementation of IHT accommodates SNP genotype compression and exploits multiple CPU cores and graphics processing units (GPUs). This allows statistical geneticists to leverage commodity desktop computers in GWAS analysis and to avoid supercomputing. Availability: Source code is freely available at https://github.com/klkeys/IHT.jl.
The association between obstetrical history and preterm birth in women with uterine anomalies

Abstract Objective: To estimate the association between obstetric history and preterm birth in women with uterine anomalies. Methods: This was a retrospective cohort study of women with uterine anomalies managed by one maternal–fetal medicine practice from 2005 to 2016. Women were separated into three groups based on their most recent pregnancy outcome: preterm birth <37 weeks, nulliparous, and term birth. Delivery outcomes were compared across the three groups, with the primary outcome being preterm birth <37 weeks. A subgroup analysis was performed in women with major uterine anomalies (unicornuate, bicornuate, and didelphys). Results: A total of 283 women with uterine anomalies were included. Preterm birth <37 weeks was 60.4% in women with prior preterm birth versus 18.2% in nulliparous women, versus 15.8% in women with a prior term birth (p < .001). The difference between nulliparous women and women with a prior term birth was not significant (p = .635). Among the 118 women with major uterine anomalies, the likelihood of preterm birth was also highest in the prior preterm birth group (71.4 versus 26.1 versus 25.0%, p < .001), and the difference between nulliparous women and women with a prior term birth was not significant (p = .906). Conclusions: In women with uterine abnormalities, a prior preterm birth is significantly associated with recurrent preterm birth. However, a prior term birth does not lower the risk of preterm birth as compared to nulliparous women.
Improved Score Statistics for Meta-analysis in Single-variant and Gene-level Association Studies

Meta-analysis is now an essential tool for genetic association studies, allowing these to combine large studies and greatly accelerating the pace of genetic discovery. Although the standard meta-analysis methods perform equivalently as the more cumbersome joint analysis under ideal settings, they result in substantial power loss under unbalanced settings with various case-control ratios. Here, we investigate why the standard meta-analysis methods lose power under unbalanced settings, and further propose a novel meta-analysis method that performs as efficiently as joint analysis under general settings. Our proposed method can accurately approximate the score statistics obtainable by joint analysis, for both linear and logistic regression models, with and without covariates. In addition, we propose a novel approach to adjust for population stratification by correcting for known population structures through minor allele frequencies (MAFs). In the simulated gene-level association studies under unbalanced settings, our method recovered up to 85% power loss caused by the standard method. We further showed the power gain of our method in gene-level association studies with 26 unbalanced real studies of Age-related Macular Degeneration (AMD). In addition, we took the meta-analysis of three studies of type 2 diabetes (T2D) as an example to discuss the challenges of meta-analyzing multi-ethnic samples. In summary, we propose improved single-variant score statistics in meta-analysis, requiring “accurate” population-specific MAFs for multi-ethnic studies. These improved score statistics can be used to construct both single-variant and gene-level association studies, providing a useful framework for ensuring well-powered, convenient, cross-study analyses.