Real-World Treatment Patterns Among Patients with Type 2 Diabetes Mellitus Initiating Treatment with Oral Semaglutide.

INTRODUCTION: The treatment landscape for type 2 diabetes mellitus (T2DM) is complex and constantly evolving, and real-world evidence of prescribing patterns is limited. The objectives of this study were to characterize lines of therapy (LOTs), calculate the length of time spent on each LOT, and identify the reasons for the LOT end among patients who initiated oral semaglutide for T2DM. METHODS: This retrospective, claims-based study included commercial and Medicare Advantage adults with T2DM. Data from November 1, 2019, and June 30, 2020, were obtained from Optum Research Database. Patients with ≥ 1 claim for oral semaglutide and continuous health plan enrollment for ≥ 12 months prior to (baseline period) and ≥ 6 months following (follow-up period) the date of the first oral semaglutide claim were included. LOT 1 began on the date of the first oral semaglutide claim. The start date of any subsequent LOTs was the date of the first claim for an additional non-insulin anti-diabetic drug class or a reduction in drug class with use of commitment medications. The LOT ended at the first instance of medication class discontinuation, change in regimen or end of follow-up. RESULTS: Of the 1937 patients who initiated oral semaglutide, 950 (49.0%) remained on their initial regimen over the 6-month follow-up period, 844 (43.6%) had at least one subsequent LOT, and 89 (4.6%) had at least two subsequent LOTs. Among patients with more than one LOT, approximately 20%-25% used oral semaglutide as monotherapy or combination therapy during LOTs 2 and 3. Metformin was frequently used during treatment across all LOTs. CONCLUSION: This study provides insight for physicians and payers into the real-world prescribing practices within the first 6 months following oral semaglutide initiation and fills the gap in understanding the frequency of regimen changes in the constantly evolving and complex environment of T2DM care.

Type 2 diabetes mellitus is a disease which, over time, can cause higher than normal levels of sugar in the blood (hyperglycemia) which can be harmful if not treated. Treatment for type 2 diabetes mellitus can be complex, and how doctors prescribe medications is always changing. For some people with type 2 diabetes mellitus who are overweight or obese, it is recommended for patients to use certain medications that can help with weight management such as semaglutide and metformin. This study aims to fill gaps in current treatment knowledge about type 2 diabetes mellitus patients and their treatment of oral semaglutide. Researchers in this study explored how patients treated with oral semaglutide differentiated among line of therapies, how long patients stuck to them and why they stopped. The study found that those patients who started with oral semaglutide, almost half of those patients stuck to their initial treatment plan for the entire 6 months. When it came to the top ten treatment plans, about 20% of patients used oral semaglutide alone and about 25% of patients used oral semaglutide plus an additional treatment option. Metformin was frequently used during treatment across all line of therapies. There is little information on the real-life setting of treatment after the start of therapy for type 2 diabetes mellitus. The results from this study show what happens when patients start using oral semaglutide and helps healthcare providers understand how often treatment plans can change in type 2 diabetes mellitus care.

Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: a review of the BCL11B-associated phenotypes from the genetic perspective.

The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating the expression of numerous genes involved in several pathways. Monoallelic defects in the BCL11B gene leading to loss-of-function are associated with a wide spectrum of phenotypes, including neurological disorders with or without immunological features and susceptibility to hematological malignancies. From the genetic point of view, the landscape of BCL11B mutations reported so far does not fully explain the genotype-phenotype correlation. In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.

Real-world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide.

AIM: To describe the change in glycated haemoglobin (HbA1c) among patients with type 2 diabetes following treatment with a 7 or 14 mg maintenance dose of oral semaglutide. MATERIALS AND METHODS: This retrospective, claims-based study included adult patients with type 2 diabetes with a pre-index HbA1c of ≥7%, initiating treatment with oral semaglutide between 1 November 2019 and 30 June 2020; the patients had continuous health plan enrolment for ≥12 months before (pre-index) and ≥6 months following (post-index) the date of the first oral semaglutide claim (index). Patients were required to have a maintenance dose of 7 or 14 mg. Pre-index demographic and clinical characteristics were captured, as were doses at initiation and prescriber specialty. The change in HbA1c between the latest post-index and pre-index HbA1c measurements was calculated among all patients and among those with ≥90 days of continuous treatment (persistent patients). RESULTS: This study included 520 patients, most of whom had a complex medical history, experienced a range of comorbidities and received an average of 11.5 different classes of medications during the pre-index period. The mean HbA1c reduction during the 6-month post-initiation period was 1.2% (p < .001) for all patients and 1.4% (p < .001) for persistent patients. CONCLUSIONS: In this real-world study, patients with a pre-index HbA1c ≥7% who initiated treatment with oral semaglutide with a 7 or 14 mg maintenance dose had significantly lower HbA1c levels following treatment.

Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings.

Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.

Characterizing obesity in a large health care delivery system.

OBJECTIVES: To characterize the prevalence of obesity and associated health care use within an integrated health care system in California. STUDY DESIGN: Cross-sectional study using electronic health records. METHODS: Primary care patients 18 years and older receiving care at Sutter Health between 2015 and 2020 were included in the study. Obesity was classified and health care utilization was ascertained at index and during the follow-up periods. Differences in prevalence by demographic and clinical characteristics among patients with and without obesity were assessed. Logistic regression was used to estimate the relationship between obesity class and health care utilization (outpatient encounters). RESULTS: Of the 1,094,790 primary care patients included in the analysis, 35% were classified as having obesity, defined as a body mass index of 30 kg/m2 or more or 25 kg/m2 or more for Asian individuals. Obesity prevalence was greater in Hispanic patients (46%) than in non-Hispanic White patients (30%). Patients without obesity had fewer outpatient visits (mean [SD], 3.7 [3.8]) than those with class 1 (4.1 [4.0]), class 2 (4.6 [4.4]), and class 3 (5.2 [4.8]) obesity. In the fully adjusted regression model, the odds of being a high utilizer among patients with obesity were 1.1 (class 1), 1.2 (class 2), and 1.3 (class 3) times that of patients without obesity (P < .001). CONCLUSION: Obesity prevalence is high among patients in the Sutter Health system, varying by race/ethnicity, and was associated with increased outpatient visit utilization. There is a need for greater awareness of the impact of obesity and the specific patient populations affected by the disease.

Is a sFlt-1/PlGF cutoff of 38 suitable to predict adverse outcomes in pregnancies with abnormal uterine artery Doppler velocimetry in the second trimester?

OBJECTIVE: To determine the optimal cutoff value for the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio to predict maternal and fetal adverse events in pregnancies with uterine artery Doppler scans results above the 95th percentile in the late second trimester. STUDY DESIGN: Retrospective, observational cohort study on 116 asyntomatic patients with abnormal uterine artery Doppler scans at gestational week 25. The sFlt-1/PlGF ratio was determined within the weeks 25 to 29 of gestation and ROC curve analysis performed. The diagnostic validity of different cutoff values to predict severe maternal and fetal complications, i.e. preeclampsia, fetal growth restriction, placental abruption, and fetal death, was analyzed. MAIN OUTCOME MEASURES: An ideal cutoff for sFlt-1/PlGF ratios in pregnancies with abnormal uterine artery Doppler in the second trimester. RESULTS: Applying a cutoff point of 38, the area under the ROC curve was 0.89, generally considered low risk in fetal and maternal complication prediction. The sensitivity was 32.1%, the specificity 98.4%, the positive predictive value (PPV) 94.4%, and the negative predictive value (NPV) 63.3%. A cutoff value of 10, leading to the highest Youden index, performed best at detecting overall complications, increasing sensitivity to 69.8% and the NPV to 76.8%. at the cost of a reduced specificity and PPV. CONCLUSIONS: In pregnancies with abnormal uterine artery Doppler in the second trimester, an sFlt-1/PlGF cutoff value greater than equal to 38 improves its predictive power for adverse events.

Ulcerative colitis induced by obinutuzumab in a patient treated for a folicular lymphoma.

An increasing use of immunomodulatory drugs has led to a corresponding increase in treatment-related pathologies such as inflammatory bowel disease. Here, we present a case of ulcerative colitis due to Obinutuzumab, an antiCD20 monoclonal approved for the treatment of Non-Hodgkin lymphomas.

Real-World Hemoglobin A1c Changes, Prescribing Provider Types, and Medication Dose Among Patients with Type 2 Diabetes Mellitus Initiating Treatment with Oral Semaglutide.

INTRODUCTION: Given the lack of real-world data on oral semaglutide use outside clinical trials, the purpose of this study was to describe dose, prescriber specialty, and change in hemoglobin A1c (HbA1c) after 6 months of oral semaglutide treatment for patients with type 2 diabetes mellitus (T2DM). METHODS: This was a retrospective study among adult patients with T2DM with ≥ 1 claim for oral semaglutide between November 1, 2019`1-June 30, 2020. Patients had continuous health plan enrollment ≥ 12 months prior to (pre-index) and ≥ 6 months following (post-index) the date of the first oral semaglutide claim (index). Dose at initiation and specialty of the prescribing provider were captured. Change in HbA1c between the last post- and pre-index HbA1c measurement was calculated. Patients were stratified by pre-index HbA1c ≥ 9% (poorly controlled) and HbA1c < 9%. RESULTS: A total of 744 HbA1c < 9% and 268 poorly controlled patients were included in the study. Most patients had an initial oral semaglutide dose of 7 mg (49.3%) or 3 mg (42.9%), prescribed most frequently by a primary care provider (27.8%). Mean HbA1c reduction was 0.8% (p < 0.001). Patients with poorly controlled T2DM had greater HbA1c reductions than patients with HbA1c < 9% (2.0% versus 0.4%, p < 0.001). Patients persistent with oral semaglutide (≥ 90 days continuous treatment) had a mean HbA1c reduction of 0.9% (p < 0.001); persistent patients with poorly controlled T2DM had a mean reduction of 2.5%. CONCLUSIONS: Patients with T2DM in this study experienced significant reductions in HbA1c within 6 months following initiation of oral semaglutide. Patients with a higher starting HbA1c experienced greater HbA1c reductions. The initial dose of oral semaglutide was higher than prescribing instructions indicated for more than half of the study patients.

Morphological performance and seasonal pattern of water relations and gas exchange in Pistacia lentiscus plants subjected to salinity and water deficit.

Soil water deficit and salinity represent a major factor impacting plant survival and agricultural production. The frequency and severity of both abiotic stresses are expected to increase in a context of climate change, especially in arid and semi-arid regions. This work studied the growth pattern, biomass and mineral distribution and the seasonal pattern of water status, photosynthetic rate and stomatal conductance in plant of Pistacia lentiscus grown under different levels of water deficit and salinity. P. lentiscus plants growing under greenhouse conditions were subjected to four irrigation treatments during 11 months: control (C, 1 dS m-1), moderate water deficit (MW, 1dS m-1, 60% of the control), severe water deficit (SW, 1 dS m-1, 40% of the control) and saline (S, 4dS m-1). The results show that Pistacia lentiscus plants were more affected by deficit irrigation than salinity. Deficit irrigation and salinity inhibited plant height, with reductions of 20%, 22% and 35% for S, MW and SW, respectively. Total leaf area was not modified by effect of the treatments, with the result that plant compactness increased in MW. The salt stressed plants only showed lower relative growth rate at the end of the experiment. Plants responded to saline or drought stress by increasing their osmotic adjustment, which was more pronounced under salinity. Saline plants had the highest values in Na+ and Cl- ions and the lowest values for K+/Na+ and Ca2+/Na+ ratios in leaves and stems, which is correlated with a decrease in growth, stomatal conductance, photosynthesis and stem water potential, and can be used as a diagnostic tool to assess plant tolerance to salinity stress. As a measure of plant hydration, relative water content was more sensitive to deficit irrigation than salinity, being a good indicator of water stress. P. lentiscus plants subjected to both deficit irrigation treatments exhibited an increase in their intrinsic water use efficiency, which is an important adaptation for plants growing in environments with water scarcity.

Impact of sampling location and aging on the Longissimus thoracis et lumborum muscle proteome of dry-aged beef.

This study aimed to explore the differences in the proteome and molecular pathways between two sampling locations (external, internal) of bovine Longissimus thoracis et lumborum (LTL) muscles at 0, 21, and 28 days of dry-aging (i.e. 3, 24, and 31 days post-mortem). It further assessed the impact of post-mortem aging on the meat proteome changes and the biological processes at interplay. Proteins related to defence response to bacterium and regulation of viral entry into host cell were identified to be more abundant on the external location before dry-aging, which may be associated to the oxidative conditions and microbial activity to which post-mortem muscle is exposed during dressing, chilling, and/or quartering of the carcasses. This highlights the relevance of sampling from interior tissues when searching for meat quality biomarkers. As dry-aging progressed, the meat proteome and related biological processes changed differently between sampling locations; proteins related to cell-cell adhesion and ATP metabolic processes pathways were revealed in the external location at 21 and 28 days, respectively. On the other hand, the impact of aging on the proteome of the interior meat samples, evidenced that muscle contraction and structure together with energy metabolism were the major pathways driving dry-aging. Additionally, aging impacted other pathways in the interior tissues, such as regulation of calcium import, neutrophil activation, and regeneration. Overall, the differences in the proteome allowed discriminating the three dry-aging times, regardless of the sampling location. Several proteins were proposed for validation as robust biomarkers to monitor the aging process (tenderization) of dry-aged beef: TTN, GRM4, EEF1A1, LDB3, CILP2, TNNT3, GAPDH, SERPINI1, and OMD.

Influence of meat sample geometry on dehydration dynamics during dry-aging of beef.

Meat geometry may impact on the dehydration kinetics during dry-aging influencing the drying rate and, potentially, aspects of meat quality. In this study, three meat geometries (slices, steaks and sections) were prepared from three bovine Longissimuss thoracis et lumborum at 3 days post-mortem and were dry-aged at 2 °C, 75% relative humidity with an airflow of 0.5-2.0 m/s for 22 days (slices), 48 days (sections) and 49 days (steaks). Weights were recorded during dry-aging and drying curves were obtained for the three geometries, with the larger sections showing limited dehydration due to internal resistance to moisture migration from the core to the surface. Seven thin-layer equations were fitted to the dehydration data in order to model the drying kinetics during dry-aging. Thin-layer models described reliably the drying kinetics of the three geometries. In general, reduced k values (h-1) reflected the lower drying rates as thickness increased. The Midilli model provided the best fit for all geometries. Proximate analyses of the three geometries and bloomed colour of sections were measured at the start and the end of the dry-aging period. Moisture loss during dry-aging led to the concentration of protein, fat and ash contents; while no significant differences were found for L*, a* and b* values of sections before and after the dry-aging process. In addition, moisture content, water activity (aw) and LF-NMR measurements were taken at different locations within beef sections to further explore water dynamics during dry-aging.

Meningitis por Listeria: serie de casos en un hospital de tercer nivel y utilidad de las nuevas técnicas de diagnóstico microbiológico

Introducción: La meningitis por Listeria monocytogenes (MLM) es una entidad grave con complicaciones a corto plazo. La reacción de polimerasa en cadena (RPC) puede ayudar a mejorar su diagnóstico y pronóstico. Objetivos: Conocer las características de los pacientes diagnosticados de meningitis por L. monocytogenes en los últimos años, a través de diferentes métodos microbiológicos. Pacientes y Métodos: Serie de casos de pacientes adultos ingresados con MLM en el Hospital Clínico San Carlos, Madrid, España, durante doce años (2009-2021). Se describieron variables epidemiológicas, clínicas, microbiológicas, radiológicas y terapéuticas. Resultados: Se registraron doce pacientes con MLM (edad media 67,5 años, 75% varones). En ocho se obtuvo un cultivo positivo a L. monocytogenes. La RPC en líquido cefalorraquídeo (LCR) fue positiva en los dos casos en los que se realizó la prueba. El tratamiento dirigido en todos los casos fue ampicilina durante 21 días. Se registraron complicaciones en un cuarto de los casos. Del total de pacientes uno falleció. Conclusiones: La MLM es una enfermedad poco frecuente y de difícil diagnóstico. En nuestra serie de casos los dos pacientes diagnosticados por RPC tuvieron resultado de cultivo de LCR negativo, y presentaron buena evolución. La determinación de RPC podría permitir diagnosticar un mayor número de casos y con mayor precocidad.

Background: Listeria monocytogenes meningitis (LMM) is a serious entity with short-term complications. Polymerase chain reaction (PCR) can help to improve its diagnosis and prognosis. Aim: To know the characteristics of patients diagnosed with meningitis by L. monocytogenes in recent years, through different microbiological methods. Methods: Case series of adult patients admitted with LMM at the Hospital Clínico San Carlos of Madrid, Spain, during twelve years (2009-2021). Epidemiological, clinical, microbiological, radiological and therapeutic variables were described. Results: Twelve patients with LMM were recorded (mean age 67.5 years, 75% male). Eight had a positive culture for L. monocytogenes. cerebrospinal fluid (CSF) PCR was positive in the two cases in which the test was performed. Treatment in all cases was ampicillin for 21 days. Complications were recorded in a quarter of the cases. One patient died. Conclusions: LMM is a rare and difficult to diagnose disease. In our series of cases, the two patients diagnosed by PCR had negative CSF culture results, and presented good evolution. PCR determination could allow a greater number of cases to be diagnosed earlier.

Aquaporin-4 Expression Switches from White to Gray Matter Regions during Postnatal Development of the Central Nervous System.

Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system and plays a fundamental role in maintaining water homeostasis there. In adult mice, AQP4 is located mainly in ependymal cells, in the endfeet of perivascular astrocytes, and in the glia limitans. Meanwhile, its expression, location, and function throughout postnatal development remain largely unknown. Here, the expression of AQP4 mRNA was studied by in situ hybridization and RT-qPCR, and the localization and amount of protein was studied by immunofluorescence and western blotting, both in the brain and spinal cord. For this, wild-type mice of the C57BL/6 line, aged 1, 3, 7, 11, 20, and 60 days, and 18 months were used. The results showed a change in both the expression and location of AQP4 in postnatal development compared to those during adult life. In the early stages of postnatal development it appears in highly myelinated areas, such as the corpus callosum or cerebellum, and as the animal grows, it disappears from these areas, passing through the cortical regions of the forebrain and concentrating around the blood vessels. These findings suggest an unprecedented possible role for AQP4 in the early cell differentiation process, during the first days of life in the newborn animal, which will lead to myelination.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

ZDHHC15 as a candidate gene for autism spectrum disorder.

The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.

Early progression in follicular lymphoma in the absence of histological transformation or high-risk Follicular Lymphoma International Prognostic Index still has a favourable outcome.

Although follicular lymphoma (FL) patients relapsing within 24 months after first-line treatment (POD24) have a poor prognosis, some cases show notable survival after first relapse (SF1R). We aimed to characterize the POD24 FL population and to identify the main prognostic factors at progression. We selected 162 POD24 patients (80F; median age at first relapse 59 years) from a cohort of 1067 grades 1-3a FL-treated patients. The remaining 905 patients treated with first-line immunochemotherapy and diagnosed during the same period were used to compare outcomes in terms of survival. After a median follow-up of 11.0 years, 96 patients died (10y-SF1R of 40%). Age over 60 years (p < 0.001), high lactate dehydrogenase (LDH) (p < 0.001), haemoglobin (Hb) less than 120 g/L (p < 0.001), advanced stage (p < 0.001), high-risk Follicular Lymphoma International Prognostic Index (FLIPI) (p < 0.001), histological transformation (HT) (p < 0.001) and reaching less than complete response (CR) after salvage therapy (p < 0.001), predicted poor SF1R at relapse. In multivariate analysis only high-risk FLIPI and HT maintained prognostic significance for SF1R. POD24 patients not transformed and with low/intermediate FLIPI at relapse behaved better than the remaining cases. POD24 patients showed an excess mortality of 38% compared to the general population. Although outcome of POD24 FL patients is poor, a considerable group of them (low/intermediate FLIPI and not transformed at first relapse) behave better.

Over-The-Scope clip closure of an acquired bronchoesophageal fistula secondary to an esophageal diverticulum.

Esophagorespiratory fistula is a rare entity that occurs as a result of malignant and non-malignant causes. This condition is associated with high morbidity and mortality. Surgical repair has traditionally been the most common treatment and self-expandable metal stent are the first choice among non-surgical techniques. Here, we report a non-malignant bronchoesophageal fistula secondary to an esophageal diverticulum that was successfully closed using an over-the-scope clip.

PhenoExam: gene set analyses through integration of different phenotype databases.

BACKGROUND: Gene set enrichment analysis (detecting phenotypic terms that emerge as significant in a set of genes) plays an important role in bioinformatics focused on diseases of genetic basis. To facilitate phenotype-oriented gene set analysis, we developed PhenoExam, a freely available R package for tool developers and a web interface for users, which performs: (1) phenotype and disease enrichment analysis on a gene set; (2) measures statistically significant phenotype similarities between gene sets and (3) detects significant differential phenotypes or disease terms across different databases. RESULTS: PhenoExam generates sensitive and accurate phenotype enrichment analyses. It is also effective in segregating gene sets or Mendelian diseases with very similar phenotypes. We tested the tool with two similar diseases (Parkinson and dystonia), to show phenotype-level similarities but also potentially interesting differences. Moreover, we used PhenoExam to validate computationally predicted new genes potentially associated with epilepsy. CONCLUSIONS: We developed PhenoExam, a freely available R package and Web application, which performs phenotype enrichment and disease enrichment analysis on gene set G, measures statistically significant phenotype similarities between pairs of gene sets G and G' and detects statistically significant exclusive phenotypes or disease terms, across different databases. We proved with simulations and real cases that it is useful to distinguish between gene sets or diseases with very similar phenotypes. Github R package URL is https://github.com/alexcis95/PhenoExam . Shiny App URL is https://alejandrocisterna.shinyapps.io/phenoexamweb/ .