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Science (New York, N.Y.) Feb 2015According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of...
According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes.
Topics: Comorbidity; Disease; Genetic Predisposition to Disease; Humans; Information Services; Protein Interaction Maps
PubMed: 25700523
DOI: 10.1126/science.1257601 -
Physiological Reviews Oct 2014Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later... (Review)
Review
Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.
Topics: Cardiovascular Diseases; Chronic Disease; Disease; Epigenomics; Human Development; Humans; Life Style; Risk Factors; Time Factors
PubMed: 25287859
DOI: 10.1152/physrev.00029.2013 -
Briefings in Bioinformatics Sep 2011Orthology is one of the most important tools available to modern biology, as it allows making inferences from easily studied model systems to much less tractable systems... (Review)
Review
Orthology is one of the most important tools available to modern biology, as it allows making inferences from easily studied model systems to much less tractable systems of interest, such as ourselves. This becomes important not least in the study of genetic diseases. We here review work on the orthology of disease-associated genes and also present an updated version of the InParanoid-based disease orthology database and web site OrthoDisease, with 14-fold increased species coverage since the previous version. Using this resource, we survey the taxonomic distribution of orthologs of human genes involved in different disease categories. The hypothesis that paralogs can mask the effect of deleterious mutations predicts that known heritable disease genes should have fewer close paralogs. We found large-scale support for this hypothesis as significantly fewer duplications were observed for disease genes in the OrthoDisease ortholog groups.
Topics: Animals; Databases, Genetic; Disease; Disease Models, Animal; Genetic Predisposition to Disease; Genome; Humans; Phylogeny; Software; Species Specificity
PubMed: 21565935
DOI: 10.1093/bib/bbr024 -
Annual Review of Pathology Jan 2020Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and... (Review)
Review
Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and from adult stem cells, the latter being the subject of this review. Organoids derived from adult stem cells exploit the tissue regeneration process that is driven by these cells, and they can be established directly from the healthy or diseased epithelium of many organs. Organoids are amenable to any experimental approach that has been developed for cell lines. Applications in experimental biology involve the modeling of tissue physiology and disease, including malignant, hereditary, and infectious diseases. Biobanks of patient-derived tumor organoids are used in drug development research, and they hold promise for developing personalized and regenerative medicine. In this review, we discuss the applications of adult stem cell-derived organoids in the laboratory and the clinic.
Topics: Adult; Adult Stem Cells; Cell Biology; Cell- and Tissue-Based Therapy; Disease; Humans; Organoids; Pluripotent Stem Cells; Regenerative Medicine
PubMed: 31550983
DOI: 10.1146/annurev-pathmechdis-012419-032611 -
Nucleic Acids Research Jan 2019The Human Disease Ontology (DO) (http://www.disease-ontology.org), database has undergone significant expansion in the past three years. The DO disease classification...
The Human Disease Ontology (DO) (http://www.disease-ontology.org), database has undergone significant expansion in the past three years. The DO disease classification includes specific formal semantic rules to express meaningful disease models and has expanded from a single asserted classification to include multiple-inferred mechanistic disease classifications, thus providing novel perspectives on related diseases. Expansion of disease terms, alternative anatomy, cell type and genetic disease classifications and workflow automation highlight the updates for the DO since 2015. The enhanced breadth and depth of the DO's knowledgebase has expanded the DO's utility for exploring the multi-etiology of human disease, thus improving the capture and communication of health-related data across biomedical databases, bioinformatics tools, genomic and cancer resources and demonstrated by a 6.6× growth in DO's user community since 2015. The DO's continual integration of human disease knowledge, evidenced by the more than 200 SVN/GitHub releases/revisions, since previously reported in our DO 2015 NAR paper, includes the addition of 2650 new disease terms, a 30% increase of textual definitions, and an expanding suite of disease classification hierarchies constructed through defined logical axioms.
Topics: Biological Ontologies; Databases, Factual; Disease; Humans; Workflow
PubMed: 30407550
DOI: 10.1093/nar/gky1032 -
Studies in History and Philosophy of... Aug 2020Although concepts of disease have received much scrutiny, the benefits of distinguishing between theoretical and clinical disease-and what is meant by those terms-may...
Although concepts of disease have received much scrutiny, the benefits of distinguishing between theoretical and clinical disease-and what is meant by those terms-may not be as readily apparent. One way of characterizing the distinction between theoretical and clinical conceptions of disease is by relying on Boorse's biostatistical theory (BST) for a conception of theoretical disease. Clinical disease could then be defined as theoretical disease that is diagnosed. Explicating this distinction provides a useful extension of the BST. The benefits of this approach are clearly and non-normatively demarcating disease from non-disease, while allowing for values and purpose to determine what criteria are used in clinical practice to represent a disease's underlying dysfunction. Through discussion of a variety of medical conditions, including polycystic ovary syndrome and type 2 diabetes mellitus, I explore how the relationship between BST-based theoretical and clinical disease could make sense of various features of clinical practice and medical theory. It could do this by lending focus to a nuanced understanding of the pathophysiological defects present in disease and the means by which they are assessed. This could contribute to making sense of revised nosologies and diagnostic criteria.
Topics: Biostatistics; Diagnosis; Disease; Humans; Models, Theoretical; Philosophy, Medical
PubMed: 32008896
DOI: 10.1016/j.shpsc.2019.101249 -
Philosophical Transactions of the Royal... Jan 2018Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in... (Review)
Review
Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory 'danger signals' for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Topics: Disease; Heat-Shock Proteins; Humans; Immunity; Immunity, Innate; Signal Transduction
PubMed: 29203707
DOI: 10.1098/rstb.2016.0522 -
Scientific Reports Sep 2016Blood-based biomarker assays have an advantage in being minimally invasive. Diagnostic and prognostic models built on peripheral blood gene expression have been reported...
Blood-based biomarker assays have an advantage in being minimally invasive. Diagnostic and prognostic models built on peripheral blood gene expression have been reported for various types of disease. However, most of these studies focused on only one disease type, and failed to address whether the identified gene expression signature is disease-specific or more widely applicable across diseases. We conducted a meta-analysis of 46 whole blood gene expression datasets covering a wide range of diseases and physiological conditions. Our analysis uncovered a striking overlap of signature genes shared by multiple diseases, driven by an underlying common pattern of cell component change, specifically an increase in myeloid cells and decrease in lymphocytes. These observations reveal the necessity of building disease-specific classifiers that can distinguish different disease types as well as normal controls, and highlight the importance of cell component change in deriving blood gene expression based models. We developed a new strategy to develop blood-based disease-specific models by leveraging both cell component changes and cell molecular state changes, and demonstrate its superiority using independent datasets.
Topics: Biomarkers; Computational Biology; Disease; Gene Expression Profiling; Humans; Oligonucleotide Array Sequence Analysis; Prognosis
PubMed: 27596246
DOI: 10.1038/srep32976 -
The ISME Journal Aug 2019Diversity indices have been routinely computed in the study of human microbiome-associated diseases (MADs). However, it is still unclear whether there is a consistent... (Meta-Analysis)
Meta-Analysis
Diversity indices have been routinely computed in the study of human microbiome-associated diseases (MADs). However, it is still unclear whether there is a consistent diversity-disease relationship (DDR) for the human MADs, and whether there are consistent differences in the taxonomic composition of microbiomes sampled from healthy versus diseased individuals. Here we reanalyzed raw data and used a meta-analysis to compare the microbiome diversity and composition of healthy versus diseased individuals in 41 comparisons extracted from 27 previously published studies of human MADs. In the DDR analysis, the average effect size across studies did not differ from zero for a comparison of healthy versus diseased individuals. In 30 of 41 comparisons (73%) there was no significant difference in microbiome diversity of healthy versus diseased individuals, or of different disease classes. For the species composition analysis (shared species analysis), the effect sizes were significantly different from zero. In 33 of 41 comparisons (80%), there were fewer OTUs (operational taxonomic units) shared between healthy and diseased individuals than expected by chance, but with 49% (20 of 41 comparisons) statistically significant. These results imply that the taxonomic composition of disease-associated microbiomes is often distinct from that of healthy individuals. Because species composition changes with disease state, some microbiome OTUs may serve as potential diagnostic indicators of disease. However, the overall species diversity of human microbiomes is not a reliable indicator of disease.
Topics: Bacteria; Biodiversity; Disease; Health; Humans; Microbiota
PubMed: 30894688
DOI: 10.1038/s41396-019-0395-y -
Practical Neurology Apr 2011The advance of medical semantics is, in general, towards causation. As knowledge increases, the common consequence is the re-definition of disease. This starts with...
The advance of medical semantics is, in general, towards causation. As knowledge increases, the common consequence is the re-definition of disease. This starts with symptoms then a disorder of structure or function, abnormalities of images, genetics or biochemistry, the ultimate aim being a specific aetiological mechanism which replaces broader descriptions. But medical terminology of diseases, diagnoses and syndromes is inherently imprecise. Careless nomenclature causes confused dialogue and communication. Symptoms of uncertain cause are commonly lumped together and given a new 'diagnostic' label which also may confuse and produce false concepts that stultify further thought and research. Such medicalisation of non-specific aggregations of symptoms should be avoided. The defining characteristics of diseases and diagnoses should be validated and agreed. The pragmatic diagnoses of 'symptom of unknown cause' or 'non-disease' are preferable to falsely labelling patients with obscure or non-existent diseases. "I tried to unveil the stillness of existence through a counteracting murmur of words, and, above all, I confused things with their names: that is belief." Jean-Paul Sartre (The Words, 1964).
Topics: Diagnosis; Disease; Eponyms; History of Medicine; Humans; Syndrome; Terminology as Topic
PubMed: 21385966
DOI: 10.1136/jnnp.2011.241802