KinMutRF: a random forest classifier of sequence variants in the human protein kinase superfamily.

BACKGROUND: The association between aberrant signal processing by protein kinases and human diseases such as cancer was established long time ago. However, understanding the link between sequence variants in the protein kinase superfamily and the mechanistic complex traits at the molecular level remains challenging: cells tolerate most genomic alterations and only a minor fraction disrupt molecular function sufficiently and drive disease. RESULTS: KinMutRF is a novel random-forest method to automatically identify pathogenic variants in human kinases. Twenty six decision trees implemented as a random forest ponder a battery of features that characterize the variants: a) at the gene level, including membership to a Kinbase group and Gene Ontology terms; b) at the PFAM domain level; and c) at the residue level, the types of amino acids involved, changes in biochemical properties, functional annotations from UniProt, Phospho.ELM and FireDB. KinMutRF identifies disease-associated variants satisfactorily (Acc: 0.88, Prec:0.82, Rec:0.75, F-score:0.78, MCC:0.68) when trained and cross-validated with the 3689 human kinase variants from UniProt that have been annotated as neutral or pathogenic. All unclassified variants were excluded from the training set. Furthermore, KinMutRF is discussed with respect to two independent kinase-specific sets of mutations no included in the training and testing, Kin-Driver (643 variants) and Pon-BTK (1495 variants). Moreover, we provide predictions for the 848 protein kinase variants in UniProt that remained unclassified. A public implementation of KinMutRF, including documentation and examples, is available online ( http://kinmut2.bioinfo.cnio.es ). The source code for local installation is released under a GPL version 3 license, and can be downloaded from https://github.com/Rbbt-Workflows/KinMut2 . CONCLUSIONS: KinMutRF is capable of classifying kinase variation with good performance. Predictions by KinMutRF compare favorably in a benchmark with other state-of-the-art methods (i.e. SIFT, Polyphen-2, MutationAssesor, MutationTaster, LRT, CADD, FATHMM, and VEST). Kinase-specific features rank as the most elucidatory in terms of information gain and are likely the improvement in prediction performance. This advocates for the development of family-specific classifiers able to exploit the discriminatory power of features unique to individual protein families.

The burden of disease of three food-associated heavy metals in clusters in the Danish population - Towards targeted public health strategies.

Lifestyle and sociodemographics are likely to influence dietary patterns, and, as a result, human exposure to chemical contaminants in foods and their associated health impact. We aimed to characterize subgroups of the Danish population based on diet and sociodemographic indicators, and identify those bearing a higher disease burden due to exposure to methylmercury (MeHg), cadmium (Cd) and inorganic arsenic (i-As). We collected dietary, lifestyle, and sociodemographic data on the occurrence of chemical contaminants in foods from Danish surveys. We grouped participants according to similarities in diet, lifestyle, and sociodemographics using Self-Organizing Maps (SOM), and estimated disease burden in disability-adjusted life years (DALY). SOM clustering resulted in 12 population groups with distinct characteristics. Exposure to contaminants varied between clusters and was largely driven by intake of fish, seafood and cereal products. Five clusters had an estimated annual burden >20 DALY/100,000. The cluster with the highest burden had a high proportion of women of childbearing age, with most of the burden attributed to MeHg. Individuals belonging to the top three clusters had higher education and physical activity, were mainly non-smokers and lived in urban areas. Our findings may facilitate the development of preventive strategies targeted to the most affected subgroups.