Machine learning and feature selection methods for egfr mutation status prediction in lung cancer

The evolution of personalized medicine has changed the therapeutic strategy from classical chemotherapy and radiotherapy to a genetic modification targeted therapy, and although biopsy is the traditional method to genetically characterize lung cancer tumor, it is an invasive and painful procedure for the patient. Nodule image features extracted from computed tomography (CT) scans have been used to create machine learning models that predict gene mutation status in a noninvasive, fast, and easy-to-use manner. However, recent studies have shown that radiomic features extracted from an extended region of interest (ROI) beyond the tumor, might be more relevant to predict the mutation status in lung cancer, and consequently may be used to significantly decrease the mortality rate of patients battling this condition. In this work, we investigated the relation between image phenotypes and the mutation status of Epidermal Growth Factor Receptor (EGFR), the most frequently mutated gene in lung cancer with several approved targeted-therapies, using radiomic features extracted from the lung containing the nodule. A variety of linear, nonlinear, and ensemble predictive classification models, along with several feature selection methods, were used to classify the binary outcome of wild-type or mutant EGFR mutation status. The results show that a comprehensive approach using a ROI that included the lung with nodule can capture relevant information and successfully predict the EGFR mutation status with increased performance compared to local nodule analyses. Linear Support Vector Machine, Elastic Net, and Logistic Regression, combined with the Principal Component Analysis feature selection method implemented with 70% of variance in the feature set, were the best-performing classifiers, reaching Area Under the Curve (AUC) values ranging from 0.725 to 0.737. This approach that exploits a holistic analysis indicates that information from more extensive regions of the lung containing the nodule allows a more complete lung cancer characterization and should be considered in future radiogenomic studies.This work is financed by the ERDF—European Regional Development Fund through the Operational Programme for Competitiveness and Internationalisation—COMPETE 2020 Programme and by National Funds through the Portuguese funding agency, FCT—Fundação para a Ciência e a Tecnologia within project POCI-01-0145-FEDER-030263

Comprehensive perspective for lung cancer characterisation based on AI solutions using CT images

Lung cancer is still the leading cause of cancer death in the world. For this reason, novel approaches for early and more accurate diagnosis are needed. Computer-aided decision (CAD) can be an interesting option for a noninvasive tumour characterisation based on thoracic computed tomography (CT) image analysis. Until now, radiomics have been focused on tumour features analysis, and have not considered the information on other lung structures that can have relevant features for tumour genotype classification, especially for epidermal growth factor receptor (EGFR), which is the mutation with the most successful targeted therapies. With this perspective paper, we aim to explore a comprehensive analysis of the need to combine the information from tumours with other lung structures for the next generation of CADs, which could create a high impact on targeted therapies and personalised medicine. The forthcoming artificial intelligence (AI)-based approaches for lung cancer assessment should be able to make a holistic analysis, capturing information from pathological processes involved in cancer development. The powerful and interpretable AI models allow us to identify novel biomarkers of cancer development, contributing to new insights about the pathological processes, and making a more accurate diagnosis to help in the treatment plan selection.This work is financed by the ERDF–European Regional Development Fund through the Operational Programme for Competitiveness and Internationalisation–COMPETE 2020 Programme and by National Funds through the Portuguese funding agency, FCT–Fundação para a Ciência e a Tecnologia within project POCI-01-0145-FEDER-030263

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis

Uma ação sinérgica por direitos reprodutivos: uma história sem fim

No Brasil, os direitos reprodutivos estão previstos em legislação nacional e normativas do Ministério da Saúde, devendo ser objeto de políticas públicas, e também uma agenda do movimento de mulheres desde os anos 1970. O planejamento familiar integra essas políticas, tendo como base os princípios da não coerção e escolha informada e responsável, implicando em parâmetros éticos. O Conselho Municipal de Saúde de Porto Alegre, mecanismo instituído por lei para exercer o controle social sobre essas políticas, foi instado em 2006 a assegurar os parâmetros éticos e legais quando um programa de implantes hormonais em adolescentes foi autorizado pela prefeitura sem debate no Conselho. A proposta deste artigo é refletir a partir da Ciência Política e do Feminismo sobre as estratégias utilizadas pelo movimento de mulheres para a reversão desse programa, suas alianças e argumentos, bem como as lições aprendidas. Como resultado se obteve a reversão do programa de implantes e o reposionamento do Conselho como órgão deliberativo da política de saúde.In Brazil, reproductive rights are provided for a national legislation and regulations of the Ministry of Health, should be the object of public policy, and is an agenda of women's movement since 1970 decade. Family planning integrates these policies, based on the principles of non-coercion, informed choice and responsible, resulting in ethical standards. The health council of Porto Alegre, a mechanism established by law to exercise social control over those policies, was asked in 2006 to ensure the ethical and legal parameters when a program of hormone implants in adolescents has been authorized by the city without a debate in the Council. The purpose of this paper is to discuss, from the Political Science and Feminist Theory the strategies used by the feminist movement for the reversal of this program, its alliances and arguments, as well as lessons learned. As a result is has obtained the reversal of the implants program and the deliberative body of the Health Council on health public policy

Distribution and heritability of diurnal preference (chronotype) in a rural Brazilian family-based cohort, the Baependi study

Diurnal preference (chronotype) is a useful instrument for studying circadian biology in humans. It harbours trait-like dimensions relating to circadian period and sleep homeostasis, but also has ontogenetic components (morningness increases with age). We used the Morningness-Eveningness questionnaire (MEQ) in the Baependi study, a family-based cohort study based in a small town in Minas Gerais, Brazil. The population is highly admixed and has a cohesive and conservative lifestyle. 825 individuals (497 female) aged 18-89 years (average ± SD = 46.4 ± 16.3) and belonging to 112 different families participated in this study. The average MEQ score was 63.5 ± 11.2 with a significant (P < 0.0001) linear increase with age. Morningness was significantly (P < 0.0001) higher in the rural (70.2 ± 9.8) than in the municipal zone (62.6 ± 11.1), and was also significantly (P = 0.025) higher in male (64.6 ± 10.9) than in female (62.8 ± 11.2) participants. Thus, in spite of universal access to electricity, the Baependi population was strongly shifted towards morningness, particularly in the rural zone. Heritability of MEQ score was 0.48 when adjusted for sex and age, or 0.38 when adjusted for sex, age, and residential zone. The reported MEQ score heritability is more akin to those of previous twin studies than previous family studies

Arousals are frequent and associated with exacerbated blood pressure response in patients with primary hypertension

Background\ud Spontaneous arousals are relatively common during sleep, and induce\ud hemodynamic responses. We sought to investigate the frequency and\ud magnitude of blood pressure (BP) increases triggered by spontaneous\ud arousals in patients with primary hypertension.\ud Methods\ud We conducted a study in which we divided 18 nonobese, sedentary\ud adults without sleep-disordered breathing into two groups, consisting\ud of: (i) hypertensive (HT, n = 8) patients; and (ii) normotensive (NT, n = 10)\ud controls. The groups were matched for age and body mass index. All\ud subjects underwent full polysomnography with simultaneous monitoring\ud of heart rate (HR) and beat-by-beat BP. Each subject’s BP and HR\ud were analyzed immediately before BP peaks triggered by spontaneous\ud arousals during stage 2 of nonrapid eye movement sleep.\ud Results\ud The total sleep time, sleep efficiency, and sleep structure in the two\ud study groups were similar. In contrast, the number of arousals was\ud significantly higher in the HT than in the NT group, at 25 ± 5 vs. 12 ± 3\ud events/h, respectively (P < 0.05). The HR of the HT and NT groups was\ud similar before arousal (65 ± 3 bpm vs. 67 ± 3 bpm, respectively, P < 0.01)\ud and increased significantly and similarly in the two groups upon arousal\ud (to 79 ± 6 bpm vs. 74 ± 4 bpm, respectively, P < 0.01). Systolic and diastolic\ud BPs were significantly higher throughout sleep in the HT than\ud in the NT group. During spontaneous arousals, BP increased in both\ud groups (P < 0.05). However, the magnitude of the increase in systolic BP\ud was significantly greater in the HT than in the NT group (22 ± 3 mm Hg\ud vs. 15 ± 3 mm Hg, P < 0.05).\ud Conclusions\ud Patients with hypertension who do not have sleep-disordered breathing\ud have an increased cardiovascular burden during sleep, which may\ud be due to the greater number of arousals and exacerbated systolic BP\ud response that they experience during sleep. These novel findings may\ud have cardiovascular implications in patients with hypertensionFAPESP 2010/18183–6Conselho Nacional de Pesquisa (CNPq) 301867/2010-0Fundação Zerbin

Shared Genetic Factors of Anxiety and Depression Symptoms in a Brazilian Family-Based Cohort, the Baependi Heart Study

To investigate the phenotypic and genetic overlap between anxiety and depression symptoms in an admixed population from extended family pedigrees. Participants (n = 1,375) were recruited from a cohort of 93 families (mean age±SD 42±16.3, 57% female) in the rural town of Baependi, Brazil. The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety symptoms. Heritability estimates were obtained by an adjusted variance component model. Bivariate analyses were performed to obtain the partition of the covariance of anxiety and depression into genetic and environmental components, and to calculate the genetic contribution modulating both sets of symptoms. Anxiety and depression scores were 7.49±4.01 and 5.70±3.82, respectively. Mean scores were affected by age and were significantly higher in women. Heritability for depression and anxiety, corrected for age and sex, were 0.30 and 0.32, respectively. Significant genetic correlations (ρg = 0.81) were found between anxiety and depression scores; thus, nearly 66% of the total genetic variance in one set of symptoms was shared with the other set. Our results provided strong evidence for a genetic overlap between anxiety and depression symptoms, which has relevance for our understanding of the biological basis of these constructs and could be exploited in genome-wide association studies

Heritability of semantic verbal fluency task using time-interval analysis

Individual variability in word generation is a product of genetic and environmental influences. The genetic effects on semantic verbal fluency were estimated in 1,735 participants from the Brazilian Baependi Heart Study. The numbers of exemplars produced in 60 s were broken down into time quartiles because of the involvement of different cognitive processes—predominantly automatic at the beginning, controlled/executive at the end. Heritability in the unadjusted model for the 60-s measure was 0.32. The best-fit model contained age, sex, years of schooling, and time of day as covariates, giving a heritability of 0.21. Schooling had the highest moderating effect. The highest heritability (0.17) was observed in the first quartile, decreasing to 0.09, 0.12, and 0.0003 in the following ones. Heritability for average production starting point (intercept) was 0.18, indicating genetic influences for automatic cognitive processes. Production decay (slope), indicative of controlled processes, was not significant. The genetic influence on different quartiles of the semantic verbal fluency test could potentially be exploited in clinical practice and genome-wide association studies