Learning vector representation of medical objects via EMR-driven nonnegative restricted Boltzmann machines (eNRBM)

Electronic medical record (EMR) offers promises for novel analytics. However, manual feature engineering from EMR is labor intensive because EMR is complex – it contains temporal, mixed-type and multimodal data packed in irregular episodes. We present a computational framework to harness EMR with minimal human supervision via restricted Boltzmann machine (RBM). The framework derives a new representation of medical objects by embedding them in a low-dimensional vector space. This new representation facilitates algebraic and statistical manipulations such as projection onto 2D plane (thereby offering intuitive visualization), object grouping (hence enabling automated phenotyping), and risk stratification. To enhance model interpretability, we introduced two constraints into model parameters: (a) nonnegative coefficients, and (b) structural smoothness. These result in a novel model called eNRBM (EMR-driven nonnegative RBM). We demonstrate the capability of the eNRBM on a cohort of 7578 mental health patients under suicide risk assessment. The derived representation not only shows clinically meaningful feature grouping but also facilitates short-term risk stratification. The F-scores, 0.21 for moderate-risk and 0.36 for high-risk, are significantly higher than those obtained by clinicians and competitive with the results obtained by support vector machines

Contributions of Dopamine-Related Genes and Environmental Factors to Highly Sensitive Personality: A Multi-Step Neuronal System-Level Approach

Traditional behavioral genetic studies (e.g., twin, adoption studies) have shown that human personality has moderate to high heritability, but recent molecular behavioral genetic studies have failed to identify quantitative trait loci (QTL) with consistent effects. The current study adopted a multi-step approach (ANOVA followed by multiple regression and permutation) to assess the cumulative effects of multiple QTLs. Using a system-level (dopamine system) genetic approach, we investigated a personality trait deeply rooted in the nervous system (the Highly Sensitive Personality, HSP). 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes. In addition, two environment factors (stressful life events and parental warmth) that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors. In Step 1, using ANOVA, we identified 10 polymorphisms that made statistically significant contributions to HSP. In Step 2, these polymorphism's main effects and interactions were assessed using multiple regression. This model accounted for 15% of the variance of HSP (p<0.001). Recent stressful life events accounted for an additional 2% of the variance. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be very low, p ranging from 0.001 to 0.006. Dividing these loci by the subsystems of dopamine synthesis, degradation/transport, receptor and modulation, we found that the modulation and receptor subsystems made the most significant contribution to HSP. The results of this study demonstrate the utility of a multi-step neuronal system-level approach in assessing genetic contributions to individual differences in human behavior. It can potentially bridge the gap between the high heritability estimates based on traditional behavioral genetics and the lack of reproducible genetic effects observed currently from molecular genetic studies

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

Scanning Cytometry with a LEAP: Laser-Enabled Analysis and Processing of Live Cells In Situ

Background: Scanning cytometry now has many of the features (and power) of multiparameter flow cytometry while keeping its own advantages as an imaging technology. Modern instruments combine capabilities of scanning cytometry with the ability to manipulate cells. A new technology, called LEAP (laser-enabled analysis and processing), offers a unique combination of capabilities in cell purification and selective macromolecule delivery (optoinjection). Methods: LEAP-mediated cell purification and optoinjection effects were assessed in model experiments using adherent and suspension cell types and cell mixtures plated and processed at different densities. Optoinjection effects were visualized by delivering fluorescent dextrans into cells. Results were analyzed using the LEAP instrument’s own imaging system aswell as by fluorescence and confocal microscopy. Results: Live cell samples (adherent and suspension) could be purified to 90–100% purity with 50–90% yield, causing minimal cell damage depending on the cell type and plating density. Nearly one hundred percent of the targeted cells of all cell types examined could be successfully optoinjected with dextrans of 3–70 kDa, causing no visual damage to the cells. Indirect optoinjection effects were observed on untargeted cells within 5–60 lm to targeted areas under conditions used here. Conclusions: LEAP provides solutions in cell purification and targeted macromolecule delivery for traditional and challenging applications where other methods fall short. q 2006 International Society for Analytical Cytolog