Penalized regression calibration: a method for the prediction of survival outcomes using complex longitudinal and high-dimensional data

Longitudinal and high-dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high-dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject-specific summaries of the longitudinal trajectories are derived from the fitted mixed models. Third, the time to event outcome is predicted using the subject-specific summaries as covariates in a penalized Cox model. To ensure a proper internal validation of the fitted PRC models, we furthermore develop a cluster bootstrap optimism correction procedure that allows to correct for the optimistic bias of apparent measures of predictiveness. PRC and the CBOCP are implemented in the R package pencal, available from CRAN. After studying the behavior of PRC via simulations, we conclude by illustrating an application of PRC to data from an observational study that involved patients affected by Duchenne muscular dystrophy, where the goal is predict time to loss of ambulation using longitudinal blood biomarkers.Development and application of statistical models for medical scientific researc

Biomarkers of Duchenne muscular dystrophy: current findings

Functional Genomics of Muscle, Nerve and Brain Disorder

Biomarkers of Duchenne muscular dystrophy: current findings

Functional Genomics of Muscle, Nerve and Brain Disorder

Rimeporide as a first- in-class NHE-1 inhibitor: results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

Successful use of Out-of-Frame Exon 2 Skipping induces IRES-Driven expression of the N-Truncated dystrophin isoform: promising approach for treating other 5 ' Dystrophin Mutations

Most mutations that truncate the reading frame of the DMD gene result in loss of dystrophin expression and lead to the most common childhood muscle disease, the severe and progressive Duchenne muscular dystrophy. However, frame-truncating mutations within the first five exons of the DMD gene typically do not result in Duchenne muscular dystrophy, but instead result in milder dystrophinopathy syndromes as originally observed in patients with very mild clinical features despite nonsense mutations in exon 1. We have previously shown that amelioration of disease severity result from the expression of a highly functional N-truncated dystrophin beginning in exon 6 of the DMD. Here we demonstrate that this protein represents a novel dystrophin isoform resulting from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid-inducible. In vitro studies with bicistronic reporter assays demonstrate translation at levels approximately 60% of the well-known viral IRES (eMCV), suggesting a relatively strong activity. Activity in humans was confirmed in patient muscle tissues using ribosome profiling and mass-spectrometric peptide sequencing. The resultant N-truncated dystrophin protein produced from this IRES, lacks the first calponin homology domain of the canonical actin binding domain 1. Nevertheless, it is highly functional, raising the possibility of the therapeutic use of this isoform. We use a novel out-of-frame exon-skipping approach to generate a truncated reading frame upstream of the IRES in both patient-derived cell lines and in a new DMD mouse model, leading to synthesis of a functional N-truncated isoform. In the mouse, this expression protects muscle from contraction-induced injury and corrects muscle force to the same level as control mice. Together these results support a novel therapeutic approach for patients with mutations within the 5' exons of DMD

Tissue-based map of the human proteome

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes.We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body

Tissue-based map of the human proteome

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes.We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body