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ObjectiveThe aim is to characterize subgroups or phenotypes of rheumatoid arthritis (RA) patients using a systems biology approach. The discovery of subtypes of rheumatoid arthritis patients is an essential research area for the improvement of response to therapy and the development of personalized medicine strategies.MethodsIn this study, 39 RA patients are phenotyped using clinical chemistry measurements, urine and plasma metabolomics analysis and symptom profiles. In addition, a Chinese medicine expert classified each RA patient as a Cold or Heat type according to Chinese medicine theory. Multivariate data analysis techniques are employed to detect and validate biochemical and symptom relationships with the classification.ResultsThe questionnaire items ‘Red joints’, ‘Swollen joints’, ‘Warm joints’ suggest differences in the level of inflammation between the groups although c-reactive protein (CRP) and rheumatoid factor (RHF) levels were equal. Multivariate analysis of the urine metabolomics data revealed that the levels of 11 acylcarnitines were lower in the Cold RA than in the Heat RA patients, suggesting differences in muscle breakdown. Additionally, higher dehydroepiandrosterone sulfate (DHEAS) levels in Heat patients compared to Cold patients were found suggesting that the Cold RA group has a more suppressed hypothalamic-pituitary-adrenal (HPA) axis function.ConclusionSignificant and relevant biochemical differences are found between Cold and Heat RA patients. Differences in immune function, HPA axis involvement and muscle breakdown point towards opportunities to tailor disease management strategies to each of the subgroups RA patient.

Principal components analysis (PCA) is used to explore the structure of data sets containing linearly related numeric variables. Alternatively, nonlinear PCA can handle possibly nonlinearly related numeric as well as nonnumeric variables. For linear PCA, the stability of its solution can be established under the assumption of multivariate normality. For nonlinear PCA, however, standard options for establishing stability are not provided. The authors use the nonparametric bootstrap procedure to assess the stability of nonlinear PCA results, applied to empirical data. They use confidence intervals for the variable transformations and confidence ellipses for the eigenvalues, the component loadings, and the person scores. They discuss the balanced version of the bootstrap, bias estimation, and Procrustes rotation. To provide a benchmark, the same bootstrap procedure is applied to linear PCA on the same data. On the basis of the results, the authors advise using at least 1,000 bootstrap samples, using Procrustes rotation on the bootstrap results, examining the bootstrap distributions along with the confidence regions, and merging categories with small marginal frequencies to reduce the variance of the bootstrap results.

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In explorative regression studies, linear models are often applied without questioning the linearity of the relations between the predictor variables and the dependent variable, or linear relations are taken as an approximation. In this study, the method of regression with optimal scaling transformations is demonstrated. This method does not require predefined nonlinear functions and results in easy-to-interpret transformations that will show the form of the relations. The method is illustrated using data from a German multicenter project on the indication criteria for inpatient or day clinic psychotherapy treatment. The indication criteria to include in the regression model were selected with the Lasso, which is a tool for predictor selection that overcomes the disadvantages of stepwise regression methods. The resulting prediction model indicates that treatment status is (approximately) linearly related to some criteria and nonlinearly related to others.