Search

Aims Allograft rejection following heart transplantation (HTx) is a serious complication even in the era of modern immunosuppressive regimens and causes up to a third of early deaths after HTx. Allograft rejection is mediated by a cascade of immune mechanisms leading to acute cellular rejection (ACR) and/or antibody‐mediated rejection (AMR). The gold standard for monitoring allograft rejection is invasive endomyocardial biopsy that exposes patients to complications. Little is known about the potential of circulating miRNAs as biomarkers to detect cardiac allograft rejection. We here present a systematic analysis of circulating miRNAs as biomarkers and predictors for allograft rejection after HTx using next‐generation small RNA sequencing. Methods and results We used next‐generation small RNA sequencing to investigate circulating miRNAs among HTx recipients (10 healthy controls, 10 heart failure patients, 13 ACR, and 10 AMR). MiRNA profiling was performed at different time points before, during, and after resolution of the rejection episode. We found three miRNAs with significantly increased serum levels in patients with biopsy‐proven cardiac rejection when compared with patients without rejection: hsa‐miR‐139‐5p, hsa‐miR‐151a‐5p, and hsa‐miR‐186‐5p. We identified miRNAs that may serve as potential predictors for the subsequent development of ACR: hsa‐miR‐29c‐3p (ACR) and hsa‐miR‐486‐5p (AMR). Overall, hsa‐miR‐486‐5p was most strongly associated with acute rejection episodes. Conclusions Monitoring cardiac allograft rejection using circulating miRNAs might represent an alternative strategy to invasive endomyocardial biopsy.

Drug effects can be unpredictable and vary widely among patients with environmental, genetic, and clinical factors. Randomized control trials (RCTs) are not sufficient to identify adverse drug reactions (ADRs), and the electronic health record (EHR) along with medical claims have become an important resource for pharmacovigilance. Among all the data collected in hospitals, laboratory tests represent the most documented and reliable data type in the EHR. Laboratory tests are at the core of the clinical decision process and are used for diagnosis, monitoring, screening, and research by physicians. They can be linked to drug effects either directly, with therapeutic drug monitoring (TDM), or indirectly using drug laboratory effects (DLEs) that affect surrogate tests. Unfortunately, very few automated methods use laboratory tests to inform clinical decision making and predict drug effects, partly due to the complexity of these time series that are irregularly sampled, highly dependent on other clinical covariates, and non-stationary. Deep learning, the branch of machine learning that relies on high-capacity artificial neural networks, has known a renewed popularity this past decade and has transformed fields such as computer vision and natural language processing. Deep learning holds the promise of better performances compared to established machine learning models, although with the necessity for larger training datasets due to their higher degrees of freedom. These models are more flexible with multi-modal inputs and can make sense of large amounts of features without extensive engineering. Both qualities make deep learning models ideal candidate for complex, multi-modal, noisy healthcare datasets. With the development of novel deep learning methods such as generative adversarial networks (GANs), there is an unprecedented opportunity to learn how to augment existing clinical dataset with realistic synthetic data and increase predictive performances. Moreover, GANs have the potential to simulate effects of individual covariates such as drug exposures by leveraging the properties of implicit generative models. In this dissertation, I present a body of work that aims at paving the way for next generation laboratory test-based clinical decision support systems powered by deep learning. To this end, I organized my experiments around three building blocks: (1) the evaluation of various deep learning architectures with laboratory test time series and their covariates with a forecasting task; (2) the development of implicit generative models of laboratory test time series using the Wasserstein GAN framework; (3) the inference properties of these models for the simulation of drug effects in laboratory test time series, and their application for data augmentation. Each component has its own evaluation: The forecasting task enabled me to explore the properties and performances of different learning architectures; the Wasserstein GAN models are evaluated with both intrinsic metrics and extrinsic tasks, and I always set baselines to avoid providing results in a "neural-network only" referential. Applied machine learning, and more so with deep learning, is an empirical science. While the datasets used in this dissertation are not publicly available due to patient privacy regulation, I described pre-processing steps, hyper-parameters selection and training processes with reproducibility and transparency in mind. In the specific context of these studies involving laboratory test time series and their clinical covariates, I found that for supervised tasks, machine learning holds up well against deep learning methods. Complex recurrent architectures like long short-term memory (LSTM) do not perform well on these short time series, while convolutional neural networks (CNNs) and multi-layer perceptrons (MLPs) provide the best performances, at the cost of extensive hyper-parameter tuning. Generative adversarial networks, enabled by deep learning models, were able to generate high-fidelity laboratory test time series, and the quality of the generated samples was increased with conditional models using drug exposures as auxiliary information. Interestingly, forecasting models trained on synthetic data exclusively still retain good performances, confirming the potential of GANs in privacy-oriented applications. Finally, conditional GANs demonstrated an ability to interpolate samples from drug exposure combinations not seen during training, opening the way for laboratory test simulation with larger auxiliary information spaces. In specific cases, augmenting real training sets with synthetic data improved performances in the forecasting tasks, and could be extended to other applications where rare cases present a high prediction error.

The secondary use of electronic health records (EHR) represents unprecedented opportunities for biomedical discovery. Central to this goal is, EHR-phenotyping, also known as cohort identification, which remains a significant challenge. Complex phenotypes often require multivariate and multi-scale analyses, ultimately leading to manually created phenotype definitions. We present Ontology-driven Reports-based Phenotyping from Unique Signatures (ORPheUS), an automated approach to EHR-phenotyping. To do this we identify unique signatures of abnormal clinical pathology reports that correspond to pre-defined medical terms from biomedical ontologies. By using only the clinical pathology, or "lab", reports we are able to mitigate clinical biases enabling researchers to explore other dimensions of the EHR. We used ORPheUS to generate signatures for 858 diseases and validated against reference cohorts for Type 2 Diabetes Mellitus (T2DM) and Atrial Fibrillation (AF). Our results suggest that our approach, using solely clinical pathology reports, is an effective as a primary screening tool for automated clinical phenotyping.