Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Faraway, so close. The comparative method and the potential of non-model animals in mitochondrial research

Inference from model organisms has been the engine for many discoveries in life science, but indiscriminate generalization leads to oversimplifications and misconceptions. Model organisms and inductive reasoning are irreplaceable: there is no other way to tackle the complexity of living systems. At the same time, it is not advisable to infer general patterns from a restricted number of species, which are very far from being representative of the diversity of life. Not all models are equal. Some organisms are suitable to find similarities across species, other highly specialized organisms can be used to focus on differences. In this opinion piece, we discuss the dominance of the mechanistic/reductionist approach in life sciences and make a case for an enhanced application of the comparative approach to study processes in all their various forms across different organisms. We also enlist some rising animal models in mitochondrial research, to exemplify how non-model organisms can be chosen in a comparative framework. These taxa often do not possess implemented tools and dedicated methods/resources. However, because of specific features, they have the potential to address still unanswered biological questions. Finally, we discuss future perspectives and caveats of the comparative method in the age of ‘big data’

Conceptual graph-based knowledge representation for supporting reasoning in African traditional medicine

Although African patients use both conventional or modern and traditional healthcare simultaneously, it has been proven that 80% of people rely on African traditional medicine (ATM). ATM includes medical activities stemming from practices, customs and traditions which were integral to the distinctive African cultures. It is based mainly on the oral transfer of knowledge, with the risk of losing critical knowledge. Moreover, practices differ according to the regions and the availability of medicinal plants. Therefore, it is necessary to compile tacit, disseminated and complex knowledge from various Tradi-Practitioners (TP) in order to determine interesting patterns for treating a given disease. Knowledge engineering methods for traditional medicine are useful to model suitably complex information needs, formalize knowledge of domain experts and highlight the effective practices for their integration to conventional medicine. The work described in this paper presents an approach which addresses two issues. First it aims at proposing a formal representation model of ATM knowledge and practices to facilitate their sharing and reusing. Then, it aims at providing a visual reasoning mechanism for selecting best available procedures and medicinal plants to treat diseases. The approach is based on the use of the Delphi method for capturing knowledge from various experts which necessitate reaching a consensus. Conceptual graph formalism is used to model ATM knowledge with visual reasoning capabilities and processes. The nested conceptual graphs are used to visually express the semantic meaning of Computational Tree Logic (CTL) constructs that are useful for formal specification of temporal properties of ATM domain knowledge. Our approach presents the advantage of mitigating knowledge loss with conceptual development assistance to improve the quality of ATM care (medical diagnosis and therapeutics), but also patient safety (drug monitoring)

Chemical information matters: an e-Research perspective on information and data sharing in the chemical sciences

Recently, a number of organisations have called for open access to scientific information and especially to the data obtained from publicly funded research, among which the Royal Society report and the European Commission press release are particularly notable. It has long been accepted that building research on the foundations laid by other scientists is both effective and efficient. Regrettably, some disciplines, chemistry being one, have been slow to recognise the value of sharing and have thus been reluctant to curate their data and information in preparation for exchanging it. The very significant increases in both the volume and the complexity of the datasets produced has encouraged the expansion of e-Research, and stimulated the development of methodologies for managing, organising, and analysing "big data". We review the evolution of cheminformatics, the amalgam of chemistry, computer science, and information technology, and assess the wider e-Science and e-Research perspective. Chemical information does matter, as do matters of communicating data and collaborating with data. For chemistry, unique identifiers, structure representations, and property descriptors are essential to the activities of sharing and exchange. Open science entails the sharing of more than mere facts: for example, the publication of negative outcomes can facilitate better understanding of which synthetic routes to choose, an aspiration of the Dial-a-Molecule Grand Challenge. The protagonists of open notebook science go even further and exchange their thoughts and plans. We consider the concepts of preservation, curation, provenance, discovery, and access in the context of the research lifecycle, and then focus on the role of metadata, particularly the ontologies on which the emerging chemical Semantic Web will depend. Among our conclusions, we present our choice of the "grand challenges" for the preservation and sharing of chemical information

A Bayesian network decision model for supporting the diagnosis of dementia, Alzheimer׳s disease and mild cognitive impairment

AbstractPopulation aging has been occurring as a global phenomenon with heterogeneous consequences in both developed and developing countries. Neurodegenerative diseases, such as Alzheimer׳s Disease (AD), have high prevalence in the elderly population. Early diagnosis of this type of disease allows early treatment and improves patient quality of life. This paper proposes a Bayesian network decision model for supporting diagnosis of dementia, AD and Mild Cognitive Impairment (MCI). Bayesian networks are well-suited for representing uncertainty and causality, which are both present in clinical domains. The proposed Bayesian network was modeled using a combination of expert knowledge and data-oriented modeling. The network structure was built based on current diagnostic criteria and input from physicians who are experts in this domain. The network parameters were estimated using a supervised learning algorithm from a dataset of real clinical cases. The dataset contains data from patients and normal controls from the Duke University Medical Center (Washington, USA) and the Center for Alzheimer׳s Disease and Related Disorders (at the Institute of Psychiatry of the Federal University of Rio de Janeiro, Brazil). The dataset attributes consist of predisposal factors, neuropsychological test results, patient demographic data, symptoms and signs. The decision model was evaluated using quantitative methods and a sensitivity analysis. In conclusion, the proposed Bayesian network showed better results for diagnosis of dementia, AD and MCI when compared to most of the other well-known classifiers. Moreover, it provides additional useful information to physicians, such as the contribution of certain factors to diagnosis