Fuzzy modeling by hierarchically built fuzzy rule bases

AbstractAlthough Mamdani-type fuzzy rule-based systems (FRBSs) became successfully performing clearly interpretable fuzzy models, they still have some lacks related to their accuracy when solving complex problems. A variant of these kinds of systems, which allows to perform a more accurate model representation, are the so-called approximate FRBSs. This alternative representation still cannot avoid the problems concerning the fuzzy rule learning methods, which as prototype identification algorithms, try to extract those approximate rules from the object problem space. In this paper we deal with the previous problems, viewing fuzzy models as a class of local modeling approaches which attempt to solve a complex problem by decomposing it into a number of simpler subproblems with smooth transitions between them. In order to develop this class of models, we first propose a common framework to characterize available approximate fuzzy rule learning methods, and later we modify it by introducing a fuzzy rule base hierarchical learning methodology (FRB-HLM). This methodology is based on the extension of the simple building process of the fuzzy rule base of FRBSs in a hierarchical way, in order to make the system more accurate. This flexibilization will allow us to have fuzzy rules with different degrees of specificity, and thus to improve the modeling of those problem subspaces where the former models have bad performance, as a refinement. This approach allows us not to have to assume a fixed number of rules and to integrate the good local behavior of the hierarchical model with the global model, ensuring a good global performance

The relationship of trait-like compassion with epigenetic aging: The population-based prospective Young Finns Study

Introduction: Helping others within and beyond the family has been related to living a healthy and long life. Compassion is a prosocial personality trait characterized by concern for another person who is suffering and the motivation to help. The current study examines whether epigenetic aging is a potential biological mechanism that explains the link between prosociality and longevity. Methods: We used data from the Young Finns Study that follows six birth-cohorts from age 3–18 to 19–49. Trait-like compassion for others was measured with the Temperament and Character Inventory in the years 1997 and 2001. Epigenetic age acceleration and telomere length were measured with five DNA methylation (DNAm) indicators (DNAmAgeHorvath, IEAA_Hannum, EEAA_Hannum, DNAmPhenoAge, and DNAmTL) based on blood drawn in 2011. We controlled for sex, socioeconomic status in childhood and adulthood, and body-mass index. Results and discussion: An association between higher compassion in 1997 and a less accelerated DNAmPhenoAge, which builds on previous work on phenotypic aging, approached statistical significance in a sex-adjusted model (n = 1,030; b = −0.34; p = 0.050). Compassion in 1997 predicted less accelerated epigenetic aging over and above the control variables (n = 843; b = −0.47; p = 0.016). There was no relationship between compassion in 2001 (n = 1108/910) and any of the other four studied epigenetic aging indicators. High compassion for others might indeed influence whether an individual’s biological age is lower than their chronological age. The conducted robustness checks partially support this conclusion, yet cannot rule out that there might be a broader prosocial trait behind the findings. The observed associations are interesting but should be interpreted as weak requiring replication.Academy of Finland 286284 134309 126925 121584 124282 129378 117787 41071 322098Social Insurance Institution of FinlandCompetitive State Research Financing of the Expert Responsibility area of Kuopio, TampereCompetitive State Research Financing of the Expert Responsibility area of Kuopio, TampereJuho Vainio FoundationPaavo Nurmi FoundationFinnish Foundation for Cardiovascular ResearchFinnish Cultural Foundation Finnish IT center for scienceSigrid Juselius FoundationTampere Tuberculosis FoundationYrjoe Jahnsson FoundationEmil Aaltonen FoundationSigne and Ane Gyllenberg FoundationDiabetes Research Foundation of the Finnish Diabetes AssociationEuropean CommissionEuropean Research Council (ERC) European CommissionTampere University Hospital Supporting FoundationFinnish Society of Clinical Chemistry 755320 848146 74292

Uncovering tumour heterogeneity through PKR and nc886 analysis in metastatic colon cancer patients treated with 5-FU-based chemotherapy

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients\u27 data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data

Modeling Genetic Networks: Comparison of Static and Dynamic Models

Biomedical research has been revolutionized by high-throughput techniques and the enormous amount of biological data they are able to generate. The interest shown over network models and systems biology is rapidly raising. Genetic networks arise as an essential task to mine these data since they explain the function of genes in terms of how they influence other genes. Many modeling approaches have been proposed for building genetic networks up. However, it is not clear what the advantages and disadvantages of each model are. There are several ways to discriminate network building models, being one of the most important whether the data being mined presents a static or dynamic fashion. In this work we compare static and dynamic models over a problem related to the inflammation and the host response to injury. We show how both models provide complementary information and cross-validate the obtained results

Profile analysis and prediction of tissue-specific CpG island methylation classes

<p>Abstract</p> <p>Background</p> <p>The computational prediction of DNA methylation has become an important topic in the recent years due to its role in the epigenetic control of normal and cancer-related processes. While previous prediction approaches focused merely on differences between methylated and unmethylated DNA sequences, recent experimental results have shown the presence of much more complex patterns of methylation across tissues and time in the human genome. These patterns are only partially described by a binary model of DNA methylation. In this work we propose a novel approach, based on profile analysis of tissue-specific methylation that uncovers significant differences in the sequences of CpG islands (CGIs) that predispose them to a tissue- specific methylation pattern.</p> <p>Results</p> <p>We defined CGI methylation profiles that separate not only between constitutively methylated and unmethylated CGIs, but also identify CGIs showing a differential degree of methylation across tissues and cell-types or a lack of methylation exclusively in sperm. These profiles are clearly distinguished by a number of CGI attributes including their evolutionary conservation, their significance, as well as the evolutionary evidence of prior methylation. Additionally, we assess profile functionality with respect to the different compartments of protein coding genes and their possible use in the prediction of DNA methylation.</p> <p>Conclusion</p> <p>Our approach provides new insights into the biological features that determine if a CGI has a functional role in the epigenetic control of gene expression and the features associated with CGI methylation susceptibility. Moreover, we show that the ability to predict CGI methylation is based primarily on the quality of the biological information used and the relationships uncovered between different sources of knowledge. The strategy presented here is able to predict, besides the constitutively methylated and unmethylated classes, two more tissue specific methylation classes conserving the accuracy provided by leading binary methylation classification methods.</p

Profile analysis and prediction of tissue-specific CpG island methylation classes

Background: The computational prediction of DNA methylation has become an important topic in the recent years due to its role in the epigenetic control of normal and cancer-related processes. While previous prediction approaches focused merely on differences between methylated and unmethylated DNA sequences, recent experimental results have shown the presence of much more complex patterns of methylation across tissues and time in the human genome. These patterns are only partially described by a binary model of DNA methylation. In this work we propose a novel approach, based on profile analysis of tissue-specific methylation that uncovers significant differences in the sequences of CpG islands (CGIs) that predispose them to a tissuespecific methylation pattern. Results: We defined CGI methylation profiles that separate not only between constitutively methylated and unmethylated CGIs, but also identify CGIs showing a differential degree of methylation across tissues and cell-types or a lack of methylation exclusively in sperm. These profiles are clearly distinguished by a number of CGI attributes including their evolutionary conservation, their significance, as well as the evolutionary evidence of prior methylation. Additionally, we assess profile functionality with respect to the different compartments of protein coding genes and their possible use in the prediction of DNA methylation. Conclusion: Our approach provides new insights into the biological features that determine if a CGI has a functional role in the epigenetic control of gene expression and the features associated with CGI methylation susceptibility. Moreover, we show that the ability to predict CGI methylation is based primarily on the quality of the biological information used and the relationships uncovered between different sources of knowledge. The strategy presented here is able to predict, besides the constitutively methylated and unmethylated classes, two more tissue specific methylation classes conserving the accuracy provided by leading binary methylation classification methods.publishedVersionPeer Reviewe

Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer\u27s Association Global Consortium

Introduction: Coronavirus disease 2019 (COVID-19) has caused \u3e3.5 million deaths worldwide and affected \u3e160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer\u27s disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer\u27s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer\u27s Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a green paper to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations

Fusion of Domain Knowledge for Dynamic Learning in Transcriptional Networks

A critical challenge of the postgenomic era is to understand how genes are differentially regulated even when they belong to a given network. Because the fundamental mechanism controlling gene expression operates at the level of transcription initiation, computational techniques have been devel oped that identify cis-regulatory features and map such features into differential expression patterns. The fact that such co-regulated genes may be differentially regulated suggests that subtle differences in the shared cis-acting regulatory elements are likely significant. Thus, we carry out an exhaustive description of cis-acting regulatory features including the orientation, location and number of binding sites for a regulatory protein, the presence of binding site submotifs, the class and number of RNA polymerase sites, as well as gene expression data, which is treated as one feature among many. These features, derived from dif ferent domain sources, are analyzed concurrently, and dynamic relations are re cognized to generate profiles, which are groups of promoters sharing common features. We apply this method to probe the regulatory networks governed by the PhoP/PhoQ two-component system in the enteric bacteria Escherichia coli and Salmonella enterica. Our analysis uncovered novel members of the PhoP regulon as and the resulting profiles group genes that share underlying biologi cal that characterize the system kinetics. The predictions were experimentally validated to establish that the PhoP protein uses multiple mechanisms to control gene transcription and is a central element in a highly connected network.Ministerio de Ciencia y Tecnología BIO2004-0270-

Classification of Gene Expression Profiles: Comparison of K-means and Expectation Maximization Algorithms

Biomedical research has been revolutionized by high throughput techniques and the enormous amount of data they are able to generate. In particular technology has the capacity to monitor changes in RNA abundance for thou sands of genes simultaneously. The interest shown over microarray analysis methods has rapidly raised. Clustering is widely used in the analysis of microarray data to group genes of interest targeted from microarray experiments on the basis of similarity of expression patterns. In this work we apply two clustering algorithms, K-means and Expecta tion Maximization to particular a problem and we compare the groupings obtained on the basis of the cohesiveness of the gene products associated to the genes in each clusterMinisterio de Ciencia y Tecnología TIN-2006-12879Junta de Andalucía TIC-0278