Cochran, A. | Search bioRxiv

bioRxiv2019

Gene-Set Enrichment with Mathematical Biology (GEMB)

Gene-set analyses measure the association between a disease of interest and a set of genes related to a biological pathway. These analyses often incorporate gene network properties to account for the differential contributions of each gene. Extending this concept further, mathematical models of biology can be leveraged to define gene interactions based on biophysical principles by predicting the effects of genetic perturbations on a particular downstream function. We present a method that combines gene weights from model predictions and gene ranks from genome-wide association studies into a weighted gene-set test. Using publicly-available summary data from the Psychiatric Genetics Consortium (n=41,653; ~9) million SNPs), we examine an a priori hypothesis that intracellular calcium ion concentrations contribute to bipolar disorder. In this case study, we are able to strengthen inferences from a P-value of 0.081 to 1.7x10-4 by moving from a general calcium signaling pathway to a specific model-predicted function.

genetics↗

bioRxiv2018

A Double-Blind Pilot Dosing Study of Low Field Magnetic Stimulation (LFMS) for Treatment-Resistant Depression (TRD)

Low Field Magnetic Stimulation is a potentially rapid-acting treatment for depression with mood-enhancing effects in as little as one 20-minute session. The most convincing data for LFMS has come from treating bipolar depression. We examined whether LFMS also has rapid mood-enhancing effects in treatment-resistant major depressive disorder, and whether these effects are dose-dependent. We hypothesized that a single 20-min session of LFMS would reduce depressive symptom severity and that the magnitude of this change would be greater after three 20-min sessions than after a single 20-min session. In a double-blind randomized controlled trial, 30 participants (age 21-65) with treatment-resistant depression were randomized to three 20-minute active or sham LFMS treatments with 48 hours between treatments. Response was assessed immediately following LFMS treatment using the 6-item Hamilton Depression Rating Scale (HAMD-6), the Positive and Negative Affect Scale (PANAS) and the Visual Analog Scale. Following the third session of LFMS, the effect of LFMS on VAS and HAMD-6 was superior to sham (F(1, 24) = 7.45, p = 0.03, Holm-Bonferroni corrected; F(1,22) = 6.92, p = 0.03, Holm-Bonferroni corrected, respectively). There were no differences between sham and LFMS following the initial or second session with the effect not becoming significant until after the third session. Three 20-minute LFMS sessions were required for active LFMS to have a mood-enhancing effect for individuals with treatment-resistant depression. As this effect may be transient, future work should address dosing schedules of longer treatment course as well as biomarker-based targeting of LFMS to optimize patient selection and treatment outcomes.

clinical trials↗