Schistosoma mansoni vaccine candidates identified by unbiased phage display screening in self-cured rhesus macaques.

Schistosomiasis, a challenging neglected tropical disease, affects millions of people worldwide. Developing a prophylactic vaccine against Schistosoma mansoni has been hindered by the parasite's biological complexity. In this study, we utilized the innovative phage-display immunoprecipitation followed by a sequencing approach (PhIP-Seq) to screen the immune response of 10 infected rhesus macaques during self-cure and challenge-resistant phases, identifying vaccine candidates. Our high-throughput S. mansoni synthetic DNA phage-display library encoded 99.6% of 119,747 58-mer peptides, providing comprehensive coverage of the parasite's proteome. Library screening with rhesus macaques' antibodies, from the early phase of establishment of parasite infection, identified significantly enriched epitopes of parasite extracellular proteins known to be expressed in the digestive tract, shifting towards intracellular proteins during the late phase of parasite clearance. Immunization of mice with a selected pool of PhIP-Seq-enriched phage-displayed peptides from MEG proteins, cathepsins B, and asparaginyl endopeptidase significantly reduced worm burden in a vaccination assay. These findings enhance our understanding of parasite-host immune responses and provide promising prospects for developing an effective schistosomiasis vaccine.

Comparison between Highly Complex Location Models and GAMLSS.

This paper presents a discussion regarding regression models, especially those belonging to the location class. Our main motivation is that, with simple distributions having simple interpretations, in some cases, one gets better results than the ones obtained with overly complex distributions. For instance, with the reverse Gumbel (RG) distribution, it is possible to explain response variables by making use of the generalized additive models for location, scale, and shape (GAMLSS) framework, which allows the fitting of several parameters (characteristics) of the probabilistic distributions, like mean, mode, variance, and others. Three real data applications are used to compare several location models against the RG under the GAMLSS framework. The intention is to show that the use of a simple distribution (e.g., RG) based on a more sophisticated regression structure may be preferable than using a more complex location model.

NERI: network-medicine based integrative approach for disease gene prioritization by relative importance.

BACKGROUND: Complex diseases are characterized as being polygenic and multifactorial, so this poses a challenge regarding the search for genes related to them. With the advent of high-throughput technologies for genome sequencing, gene expression measurements (transcriptome), and protein-protein interactions, complex diseases have been sistematically investigated. Particularly, Protein-Protein Interaction (PPI) networks have been used to prioritize genes related to complex diseases according to its topological features. However, PPI networks are affected by ascertainment bias, in which more studied proteins tend to have more connections, degrading the results quality. Additionally, methods using only PPI networks can provide only static and non-specific results, since the topologies of these networks are not specific of a given disease. RESULTS: The goal of this work is to develop a methodology that integrates PPI networks with disease specific data sources, such as GWAS and gene expression, to find genes more specific of a given complex disease. After the integration of PPI networks and gene expression data, the resulting network is used to connect genes related to the disease through the shortest paths that have the greatest concordance between their gene expressions. Both case and control expression data are used separately and, at the end, the most altered genes between the two conditions are selected. To evaluate the method, schizophrenia was adopted as case study. CONCLUSION: Results show that the proposed method successfully retrieves differentially coexpressed genes in two conditions, while avoiding the bias from literature. Moreover we were able to achieve a greater concordance in the selection of important genes from different microarray studies of the same disease and to produce a more specific gene set related to the studied disease.

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch.

Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3' UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.

Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial.

IMPORTANCE: Select cases of intractable obsessive-compulsive disorder (OCD) have undergone neurosurgical ablation for more than half a century. However, to our knowledge, there have been no randomized clinical trials of such procedures for the treatment of any psychiatric disorder. OBJECTIVE: To determine the efficacy and safety of a radiosurgery (gamma ventral capsulotomy [GVC]) for intractable OCD. DESIGN, SETTING, AND PARTICIPANTS: In a double-blind, placebo-controlled, randomized clinical trial, 16 patients with intractable OCD were randomized to active (n = 8) or sham (n = 8) GVC. Blinding was maintained for 12 months. After unblinding, sham-group patients were offered active GVC. INTERVENTIONS: Patients randomized to active GVC had 2 distinct isocenters on each side irradiated at the ventral border of the anterior limb of the internal capsule. The patients randomized to sham GVC received simulated radiosurgery using the same equipment. MAIN OUTCOMES AND MEASURES: Scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression-Improvement (CGI-I) Scale. Response was defined as a 35% or greater reduction in Y-BOCS severity and "improved" or "much improved" CGI-I ratings. RESULTS: Three of 8 patients randomized to active treatment responded at 12 months, while none of the 8 sham-GVC patients responded (absolute risk reduction, 0.375; 95% CI, 0.04-0.71). At 12 months, OCD symptom improvement was significantly higher in the active-GVC group than in the sham group (Y-BOCS, P = .046; Dimensional Y-BOCS, P = .01). At 54 months, 2 additional patients in the active group had become responders. Of the 4 sham-GVC patients who later received active GVC, 2 responded by post-GVC month 12. The most serious adverse event was an asymptomatic radiation-induced cyst in 1 patient. CONCLUSIONS AND RELEVANCE: Gamma ventral capsulotomy benefitted patients with otherwise intractable OCD and thus appears to be an alternative to deep-brain stimulation in selected cases. Given the risks inherent in any psychiatric neurosurgery, such procedures should be conducted at specialized centers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01004302.

Brazilian-Portuguese translation and cross cultural adaptation of the activities-specific balance confidence (ABC) scale.

BACKGROUND: The Activities-specific Balance Confidence (ABC) scale was developed to quantify the self-perceived level of confidence in performing specific activities without losing balance or becoming unsteady. The ABC scale has been adopted in clinical practice and in research, although cross-cultural differences may impose difficulties in its use. OBJECTIVE: To translate, cross-culturally adapt and verify the intra- and inter-rater reliability of the Brazilian-Portuguese version of the ABC scale and describe the self-perceived balance confidence of elderly Brazilian people. METHOD: The ABC scale was translated and culturally adapted. To verify the intra- and inter-rater reliability, 40 elderly individuals with ages ranging from 60 to 88 years were interviewed. The scale was administered by two raters on the same day and readministered after seven days by rater 1. To test the reliability, we used the intraclass correlation coefficient (ICC). RESULTS: Six items from the ABC scale were considered culturally, semantically or regionally inappropriate and were modified. The intra-rater reproducibility was excellent (ICC=0.94), and the inter-rater reproducibility was very good (ICC=0.80). The self-perception of balance in specific activities of the elderly was considered very good, with an average of 81.7 and scores ranging from 61.2 to 96.7. CONCLUSION: The ABC scale was translated and culturally adapted for the Brazilian population and presents good intra- and inter-rater reliability. The self-perceived balance confidence in elderly Brazilian people evaluated with the ABC scale is moderate.

Brazilian-Portuguese translation and cross cultural adaptation of the activities-specific balance confidence (ABC) scale

BACKGROUND: The Activities-specific Balance Confidence (ABC) scale was developed to quantify the self-perceived level of confidence in performing specific activities without losing balance or becoming unsteady. The ABC scale has been adopted in clinical practice and in research, although cross-cultural differences may impose difficulties in its use. OBJECTIVE: To translate, cross-culturally adapt and verify the intra- and inter-rater reliability of the Brazilian-Portuguese version of the ABC scale and describe the self-perceived balance confidence of elderly Brazilian people. METHOD: The ABC scale was translated and culturally adapted. To verify the intra- and inter-rater reliability, 40 elderly individuals with ages ranging from 60 to 88 years were interviewed. The scale was administered by two raters on the same day and readministered after seven days by rater 1. To test the reliability, we used the intraclass correlation coefficient (ICC). RESULTS: Six items from the ABC scale were considered culturally, semantically or regionally inappropriate and were modified. The intra-rater reproducibility was excellent (ICC=0.94), and the inter-rater reproducibility was very good (ICC=0.80). The self-perception of balance in specific activities of the elderly was considered very good, with an average of 81.7 and scores ranging from 61.2 to 96.7. CONCLUSION: The ABC scale was translated and culturally adapted for the Brazilian population and presents good intra- and inter-rater reliability. The self-perceived balance confidence in elderly Brazilian people evaluated with the ABC scale is moderate. .

Quality of life and discriminating power of two questionnaires in fibromyalgia patients: Fibromyalgia Impact Questionnaire and Medical Outcomes Study 36-Item Short-Form Health Survey.

BACKGROUND: Fibromyalgia is a painful syndrome characterized by widespread chronic pain and associated symptoms with a negative impact on quality of life. OBJECTIVES: Considering the subjectivity of quality of life measurements, the aim of this study was to verify the discriminating power of two quality of life questionnaires in patients with fibromyalgia: the generic Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the specific Fibromyalgia Impact Questionnaire (FIQ). METHODS: A cross-sectional study was conducted on 150 participants divided into Fibromyalgia Group (FG) and Control Group (CG) (n=75 in each group). The participants were evaluated using the SF-36 and the FIQ. The data were analyzed by the Student t-test (α=0.05) and inferential analysis using the Receiver Operating Characteristics (ROC) Curve--sensitivity, specificity and area under the curve (AUC). The significance level was 0.05. RESULTS: The sample was similar for age (CG: 47.8 ± 8.1; FG: 47.0 ± 7.7 years). A significant difference was observed in quality of life assessment in all aspects of both questionnaires (p<0.05). Higher sensibility, specificity and AUC were obtained by the FIQ (96%, 96%, 0.985, respectively), followed by the SF-36 (88%, 89% and 0.948 AUC). CONCLUSION: The FIQ presented the highest sensibility, specificity and AUC showing the most discriminating power. However the SF-36 is also a good instrument to assess quality of life in fibromyalgia patients, and we suggest that both should be used in parallel because they evaluate relevant and complementary aspects of quality of life.

Quality of life and discriminating power of two questionnaires in fibromyalgia patients: fibromyalgia Impact Questionnaire and Medical Outcomes Study 36-Item Short-Form Health Survey / A qualidade de vida e o poder de discriminação de dois questionários em pacientes com fibromialgia: fibromyalgia Impact Questionnaire e Medical Outcomes Study 36-Item Short-Form Health Survey

BACKGROUND: Fibromyalgia is a painful syndrome characterized by widespread chronic pain and associated symptoms with a negative impact on quality of life. OBJECTIVES: Considering the subjectivity of quality of life measurements, the aim of this study was to verify the discriminating power of two quality of life questionnaires in patients with fibromyalgia: the generic Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the specific Fibromyalgia Impact Questionnaire (FIQ). METHODS: A cross-sectional study was conducted on 150 participants divided into Fibromyalgia Group (FG) and Control Group (CG) (n=75 in each group). The participants were evaluated using the SF-36 and the FIQ. The data were analyzed by the Student t-test (α=0.05) and inferential analysis using the Receiver Operating Characteristics (ROC) Curve - sensitivity, specificity and area under the curve (AUC). The significance level was 0.05. RESULTS: The sample was similar for age (CG: 47.8±8.1; FG: 47.0±7.7 years). A significant difference was observed in quality of life assessment in all aspects of both questionnaires (p<0.05). Higher sensibility, specificity and AUC were obtained by the FIQ (96 percent, 96 percent, 0.985, respectively), followed by the SF-36 (88 percent, 89 percent and 0.948 AUC). CONCLUSION: The FIQ presented the highest sensibility, specificity and AUC showing the most discriminating power. However the SF-36 is also a good instrument to assess quality of life in fibromyalgia patients, and we suggest that both should be used in parallel because they evaluate relevant and complementary aspects of quality of life.

CONTEXTUALIZAÇÃO: A fibromialgia é uma síndrome dolorosa caracterizada por dor espalhada e crônica e sintomas associados com um impacto negativo na qualidade de vida. OBJETIVOS: Considerando a subjetividade da mensuração de qualidade de vida, o objetivo deste estudo foi avaliar o poder de discriminação de dois questionários que avaliam a qualidade de vida de pacientes com fibromialgia: o genérico Medical Short Form Healthy Survey (SF-36) e o específico Questionário do Impacto da Fibromialgia (QIF). MÉTODOS: Foi conduzido um estudo transversal com 150 indivíduos, divididos em dois grupos: grupo fibromialgia (FM) e grupo controle (GC) (n=75 em ambos). Os pacientes foram avaliados pelo SF-36 e pelo QIF. Na análise dos dados, utilizou-se o teste "t de Student" com α=0,05 e a Curva ROC (Receiver Operating Characteristics Curve). RESULTADOS: As amostras foram estatisticamente semelhantes para a idade - 47,8 (8,1) no GC e 47,0 (7,7) no FM - e estatisticamente diferentes em todos os aspectos dos dois questionários (SF-36 e QIF). Alta sensibilidade, especificidade e área abaixo da curva (AUC) foram obtidas com o QIF (96 por cento, 96 por cento, 0,985 respectivamente), seguido pelo SF-36 (88 por cento, 89 por cento e 0,948 AUC). CONCLUSÃO: O QIF mostrou-se mais discriminativo do que o SF-36 para avaliar a qualidade de vida de fibromiálgicos. No entanto, o SF-36 é também um bom instrumento de avaliação e sugere-se que ambos sejam usados uma vez que avaliam aspectos relevantes e complementares da qualidade de vida.

A reliable measure of similarity based on dependency for short time series: an application to gene expression networks.

BACKGROUND: Microarray techniques have become an important tool to the investigation of genetic relationships and the assignment of different phenotypes. Since microarrays are still very expensive, most of the experiments are performed with small samples. This paper introduces a method to quantify dependency between data series composed of few sample points. The method is used to construct gene co-expression subnetworks of highly significant edges. RESULTS: The results shown here are for an adapted subset of a Saccharomyces cerevisiae gene expression data set with low temporal resolution and poor statistics. The method reveals common transcription factors with a high confidence level and allows the construction of subnetworks with high biological relevance that reveals characteristic features of the processes driving the organism adaptations to specific environmental conditions. CONCLUSION: Our method allows a reliable and sophisticated analysis of microarray data even under severe constraints. The utilization of systems biology improves the biologists ability to elucidate the mechanisms underlying cellular processes and to formulate new hypotheses.

Prevalence of fibromyalgia in a low socioeconomic status population.

BACKGROUND: The aim of this study was to estimate the prevalence of fibromyalgia, as well as to assess the major symptoms of this syndrome in an adult, low socioeconomic status population assisted by the primary health care system in a city in Brazil. METHODS: We cross-sectionally sampled individuals assisted by the public primary health care system (n = 768, 35-60 years old). Participants were interviewed by phone and screened about pain. They were then invited to be clinically assessed (304 accepted). Pain was estimated using a Visual Analogue Scale (VAS). Fibromyalgia was assessed using the Fibromyalgia Impact Questionnaire (FIQ), as well as screening for tender points using dolorimetry. Statistical analyses included Bayesian Statistics and the Kruskal-Wallis Anova test (significance level = 5%). RESULTS: From the phone-interview screening, we divided participants (n = 768) in three groups: No Pain (NP) (n = 185); Regional Pain (RP) (n = 388) and Widespread Pain (WP) (n = 106). Among those participating in the clinical assessments, (304 subjects), the prevalence of fibromyalgia was 4.4% (95% confidence interval [2.6%; 6.3%]). Symptoms of pain (VAS and FIQ), feeling well, job ability, fatigue, morning tiredness, stiffness, anxiety and depression were statically different among the groups. In multivariate analyses we found that individuals with FM and WP had significantly higher impairment than those with RP and NP. FM and WP were similarly disabling. Similarly, RP was no significantly different than NP. CONCLUSION: Fibromyalgia is prevalent in the low socioeconomic status population assisted by the public primary health care system. Prevalence was similar to other studies (4.4%) in a more diverse socioeconomic population. Individuals with FM and WP have significant impact in their well being.

Higher prevalence of obsessive-compulsive spectrum disorders in rheumatic fever.

OBJECTIVE: This study aims to compare the prevalence of obsessive-compulsive spectrum disorders (OCSD) in psychiatric outpatients with and without a history of rheumatic fever (RF). METHODS: An analytical cross-sectional study assessing a large sample of consecutive psychiatric outpatients at a Brazilian private practice was conducted during a 10-year period. Psychiatric diagnoses were made by a senior psychiatrist based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Best-estimate diagnosis procedure was also performed. RESULTS: The total sample comprised 678 subjects, 13 of whom (1.92%) presented with a previous history of RF. This group showed a higher prevalence of subclinical obsessive-compulsive disorder (P=.025) and OCSD (P=.007) when compared to individuals with no such history. CONCLUSIONS: A previous history of RF was associated with OCSD. These results suggest that clinicians should be encouraged to actively investigate obsessive-compulsive symptoms and related disorders in patients with a positive history of RF.

A straightforward multiallelic significance test for the Hardy-Weinberg equilibrium law.

Much forensic inference based upon DNA evidence is made assuming Hardy-Weinberg Equilibrium (HWE) for the genetic loci being used. Several statistical tests to detect and measure deviation from HWE have been devised, and their limitations become more obvious when testing for deviation within multiallelic DNA loci. The most popular methods-Chi-square and Likelihood-ratio tests-are based on asymptotic results and cannot guarantee a good performance in the presence of low frequency genotypes. Since the parameter space dimension increases at a quadratic rate on the number of alleles, some authors suggest applying sequential methods, where the multiallelic case is reformulated as a sequence of "biallelic" tests. However, in this approach it is not obvious how to assess the general evidence of the original hypothesis; nor is it clear how to establish the significance level for its acceptance/rejection. In this work, we introduce a straightforward method for the multiallelic HWE test, which overcomes the aforementioned issues of sequential methods. The core theory for the proposed method is given by the Full Bayesian Significance Test (FBST), an intuitive Bayesian approach which does not assign positive probabilities to zero measure sets when testing sharp hypotheses. We compare FBST performance to Chi-square, Likelihood-ratio and Markov chain tests, in three numerical experiments. The results suggest that FBST is a robust and high performance method for the HWE test, even in the presence of several alleles and small sample sizes.

A straightforward multiallelic significance test for the Hardy-Weinberg equilibrium law

Much forensic inference based upon DNA evidence is made assuming Hardy-Weinberg Equilibrium (HWE) for the genetic loci being used. Several statistical tests to detect and measure deviation from HWE have been devised, and their limitations become more obvious when testing for deviation within multiallelic DNA loci. The most popular methods-Chi-square and Likelihood-ratio tests-are based on asymptotic results and cannot guarantee a good performance in the presence of low frequency genotypes. Since the parameter space dimension increases at a quadratic rate on the number of alleles, some authors suggest applying sequential methods, where the multiallelic case is reformulated as a sequence of "biallelic" tests. However, in this approach it is not obvious how to assess the general evidence of the original hypothesis; nor is it clear how to establish the significance level for its acceptance/rejection. In this work, we introduce a straightforward method for the multiallelic HWE test, which overcomes the aforementioned issues of sequential methods. The core theory for the proposed method is given by the Full Bayesian Significance Test (FBST), an intuitive Bayesian approach which does not assign positive probabilities to zero measure sets when testing sharp hypotheses. We compare FBST performance to Chi-square, Likelihood-ratio and Markov chain tests, in three numerical experiments. The results suggest that FBST is a robust and high performance method for the HWE test, even in the presence of several alleles and small sample sizes.

BayBoots: a model-free Bayesian tool to identify class markers from gene expression data.

One of the goals of gene expression experiments is the identification of differentially expressed genes among populations that could be used as markers. For this purpose, we implemented a model-free Bayesian approach in a user-friendly and freely available web-based tool called BayBoots. In spite of a common misunderstanding that Bayesian and model-free approaches are incompatible, we merged them in the BayBoots implementation using the Kernel density estimator and Rubin 's Bayesian Bootstrap. We used the Bayes error rate (BER) instead of the usual P values as an alternative statistical index to rank a class marker's discriminative potential, since it can be visualized by a simple graphical representation and has an intuitive interpretation. Subsequently, Bayesian Bootstrap was used to assess BER 's credibility. We tested BayBoots on microarray data to look for markers for Trypanosoma cruzi strains isolated from cardiac and asymptomatic patients. We found that the three most frequently used methods in microarray analysis: t-test, non-parametric Wilcoxon test and correlation methods, yielded several markers that were discarded by a time-consuming visual check. On the other hand, the BayBoots graphical output and ranking was able to automatically identify markers for which classification performance was consistent. BayBoots is available at: http://www.vision.ime.usp.br/~rvencio/BayBoots.

Bayesian model accounting for within-class biological variability in Serial Analysis of Gene Expression (SAGE).

BACKGROUND: An important challenge for transcript counting methods such as Serial Analysis of Gene Expression (SAGE), "Digital Northern" or Massively Parallel Signature Sequencing (MPSS), is to carry out statistical analyses that account for the within-class variability, i.e., variability due to the intrinsic biological differences among sampled individuals of the same class, and not only variability due to technical sampling error. RESULTS: We introduce a Bayesian model that accounts for the within-class variability by means of mixture distribution. We show that the previously available approaches of aggregation in pools ("pseudo-libraries") and the Beta-Binomial model, are particular cases of the mixture model. We illustrate our method with a brain tumor vs. normal comparison using SAGE data from public databases. We show examples of tags regarded as differentially expressed with high significance if the within-class variability is ignored, but clearly not so significant if one accounts for it. CONCLUSION: Using available information about biological replicates, one can transform a list of candidate transcripts showing differential expression to a more reliable one. Our method is freely available, under GPL/GNU copyleft, through a user friendly web-based on-line tool or as R language scripts at supplemental web-site.

Using credibility intervals instead of hypothesis tests in SAGE analysis.

MOTIVATION: Statistical methods usually used to perform Serial Analysis of Gene Expression (SAGE) analysis are based on hypothesis testing. They answer the biologist's question: 'what are the genes with differential expression greater than r with P-value smaller than P?'. Another useful and not yet explored question is: 'what is the uncertainty in differential expression ratio of a gene?'. RESULTS: We have used Bayesian model for SAGE differential gene expression ratios as a more informative alternative to hypothesis tests since it provides credibility intervals. AVAILABILITY: The model is implemented in R statistical language script and is available under GNU/GLP copyleft at supplemental web site. SUPPLEMENTARY INFORMATION: http://www.ime.usp.br/~rvencio/SAGEci/