Augmentation of Physician Assessments with Multi-Omics Enhances Predictability of Drug Response: A Case Study of Major Depressive Disorder

Abstract

This work proposes a "learning-augmented clinical assessment" workflow to sequentially augment physician assessments of patients' symptoms and their socio-demographic measures with heterogeneous biological measures to accurately predict treatment outcomes using machine learning. Across many psychiatric illnesses, ranging from major depressive disorder to schizophrenia, symptom severity assessments are subjective and do not include biological measures, making predictability in eventual treatment outcomes a challenge. Using data from the Mayo Clinic PGRN-AMPS SSRI trial as a case study, this work demonstrates a significant improvement in the prediction accuracy for antidepressant treatment outcomes in patients with major depressive disorder from 35% to 80% individualized by patient, compared to using only a physician's assessment as the predictors. This improvement is achieved through an iterative overlay of biological measures, starting with metabolites (blood measures modulated by drug action) associated with symptom severity, and then adding in genes associated with metabolomic concentrations. Hence, therapeutic efficacy for a new patient can be assessed prior to treatment, using prediction models that take as inputs, selected biological measures and physician's assessments of depression severity. Of broader significance extending beyond psychiatry, the approach presented in this work can potentially be applied to predicting treatment outcomes for other medical conditions, such as migraine headaches or rheumatoid arthritis, for which patients are treated according to subject-reported assessments of symptom severity.

Fig. 1:

The proposed analyses to establish predictability of clinical outcomes at eight weeks.

Fig. 2:

The proposed approach to integrating multiple omics (metabolomics and genomics) measures.

Fig. 3:

Estimating parameters of Gaussian mixture model for identifying clusters in the data. (a) the inference of mixtures comprising the distribution of symptom severity scores. (b) distribution of symptom severity within the clusters inferred using the sufficient statistics of components inferred in (a).

Fig. 4:

The proposed analyses to establish improved predictability in antidepressant treatment outcomes by augmenting the clinicians’ assessments with biological measures.