Faculty Bibliography

SUMMARY:We investigate convolutional neural networks (CNNs) for filtering small genomic variants in short-read DNA sequence data. Errors created during sequencing and library preparation make variant calling a difficult task. Encoding the reference genome and aligned reads covering sites of genetic variation as numeric tensors allows us to leverage CNNs for variant filtration. Convolutions over these tensors learn to detect motifs useful for classifying variants. Variant filtering models are trained to classify variants as artifacts or real variation. Visualizing the learned weights of the CNN confirmed it detects familiar DNA motifs known to correlate with real variation, like homopolymers and short tandem repeats (STR). After confirmation of the biological plausibility of the learned features we compared our model to current state-of-the-art filtration methods like Gaussian Mixture Models, Random Forests and CNNs designed for image classification, like DeepVariant. We demonstrate improvements in both sensitivity and precision. The tensor encoding was carefully tailored for processing genomic data, respecting the qualitative differences in structure between DNA and natural images. Ablation tests quantitatively measured the benefits of our tensor encoding strategy. Bayesian hyper-parameter optimization confirmed our notion that architectures designed with DNA data in mind outperform off-the-shelf image classification models. Our cross-generalization analysis identified idiosyncrasies in truth resources pointing to the need for new methods to construct genomic truth data. Our results show that models trained on heterogenous data types and diverse truth resources generalize well to new datasets, negating the need to train separate models for each data type. AVAILABILITY AND IMPLEMENTATION:This work is available in the Genome Analysis Toolkit (GATK) with the tool name CNNScoreVariants (https://github.com/broadinstitute/gatk). SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

AIM/OBJECTIVE:Evidence is emerging that prescription opioid (PO) injection is associated with increased health risks. This mixed-methods study compares the mechanics of PO and heroin injection and examines the demographic and drug-related correlates of lifetime PO injection in a sample of young people who inject drugs (PWID) in New York City (NYC). METHODS:Qualitative analysis of 46 semi-structured interviews with young adult opioid users ages 18-32. Interview segments describing PO injection were analyzed for common themes. Quantitative analysis of structured interviews with 539 young adult opioid users ages 18-29 recruited via respondent-driven sampling (RDS). Analyses are based on the subsample of 353 participants (65%) who reported having ever injected drugs. All variables were assessed via self-report, except hepatitis C virus status, which was established via rapid antibody testing. RESULTS:Participants described injecting POs and reported that preparing abuse-deterrent pills for injection is especially cumbersome, requiring extended manipulation and large amounts of water. Injecting POs, in contrast to injecting heroin, requires repeated injections per injection episode. Among RDS-recruited participants, the majority of injectors reported injecting POs, sporadically (33%) or regularly (26%), but often infrequently (≤ 7 days/month). In separate multivariable analyses controlling for syringe- and cooker-sharing, ever injecting POs was a significant predictor of testing HCV antibody-positive (AOR = 2.97) and lifetime experience of non-fatal overdose (AOR = 2.51). Ever injecting POs was independently associated with lifetime homelessness (AOR = 2.93) and having grown up in a middle-income ($51,000-100,000/year vs. ≤ $50,000/year; AOR = 1.86) or a high-income household (> $100,000/year vs. ≤ $50,000/year; AOR = 2.54). CONCLUSIONS:Even in an urban environment like NYC with widespread heroin access, most young PWID have injected POs, although less frequently than heroin. PO injection involves practices that are known to increase risk for blood-borne viral infection (e.g., repeated injections) and predicted testing HCV-positive, as well as overdose. PO injection may also serve as a marker for a subgroup of PWID at elevated risk for multiple drug use-related comorbidities. Programs that provide prevention services to PWID need to tailor harm reduction measures and messaging to the specific practices and harms associated with the injection of POs.

BACKGROUND:Syringe services programs (SSPs) are effective venues for delivering harm-reduction services to people who inject drugs (PWID). However, SSPs often face significant barriers to implementation, particularly in the absence of known human immunodeficiency virus (HIV) outbreaks. METHODS:Using an agent-based model, we simulated HIV transmission in Scott County, Indiana, a rural county with a 1.7% prevalence of injection drug use. We compared outcomes arising in the absence of an SSP, in the presence of a pre-existing SSP, and with implementation of an SSP after the detection of an HIV outbreak among PWID over 5 years following the introduction of a single infection into the network. RESULTS:In the absence of an SSP, the model predicted an average of 176 infections among PWID over 5 years or an incidence rate of 12.1/100 person-years. Proactive implementation averted 154 infections and decreased incidence by 90.3%. With reactive implementation beginning operations 10 months after the first infection, an SSP would prevent 107 infections and decrease incidence by 60.8%. Reductions in incidence were also observed among people who did not inject drugs. CONCLUSIONS:Based on model predictions, proactive implementation of an SSP in Scott County had the potential to avert more HIV infections than reactive implementation after the detection of an outbreak. The predicted impact of reactive SSP implementation was highly dependent on timely implementation after detecting the earliest infections. Consequently, there is a need for expanded proactive SSP implementation in the context of enhanced monitoring of outbreak vulnerability in Scott County and similar rural contexts.

Racial/ethnic homophily in sexual partnerships (partners share the same race/ethnicity) has been associated with racial/ethnic disparities in HIV. Structural racism may partly determine racial/ethnic homophily in sexual partnerships. This study estimated associations of racial/ethnic concentration and mortgage discrimination against Black and Latino residents with racial/ethnic homophily in sexual partnerships among 7847 people who inject drugs (PWID) recruited from 19 US cities to participate in CDC's National HIV Behavioral Surveillance. Racial/ethnic concentration was defined by two measures that respectively compared ZIP code-level concentrations of Black residents to White residents and Latino residents to White residents, using the Index of Concentration at the Extremes. Mortgage discrimination was defined by two measures that respectively compared county-level mortgage loan denial among Black applicants to White applicants and mortgage loan denial among Latino applicants to White applicants, with similar characteristics (e.g., income, loan amount). Multilevel logistic regression models were used to estimate associations. Interactions of race/ethnicity with measures of racial/ethnic concentration and mortgage discrimination were added to the final multivariable model and decomposed into race/ethnicity-specific estimates. In the final multivariable model, among Black PWID, living in ZIP codes with higher concentrations of Black vs. White residents and counties with higher mortgage discrimination against Black residents was associated with higher odds of homophily. Living in counties with higher mortgage discrimination against Latino residents was associated with lower odds of homophily among Black PWID. Among Latino PWID, living in ZIP codes with higher concentrations of Latino vs. White residents and counties with higher mortgage discrimination against Latino residents was associated with higher odds of homophily. Living in counties with higher mortgage discrimination against Black residents was associated with lower odds of homophily among Latino PWID. Among White PWID, living in ZIP codes with higher concentrations of Black or Latino residents vs. White residents was associated with lower odds of homophily, but living in counties with higher mortgage discrimination against Black residents was associated with higher odds of homophily. Racial/ethnic segregation may partly drive same race/ethnicity sexual partnering among PWID. Future empirical evidence linking these associations directly or indirectly (via place-level mediators) to HIV/STI transmission will determine how eliminating discriminatory housing policies impact HIV/STI transmission.

BACKGROUND:Adequate access to effective treatment and medication assisted therapies for opioid dependence has led to improved antiretroviral therapy adherence and decreases in morbidity among people who inject drugs (PWID), and can also address a broad range of social and public health problems. However, even with the success of syringe service programs and opioid substitution programs in European countries (and others) the US remains historically low in terms of coverage and access with regard to these programs. This manuscript investigates predictors of historical change in drug treatment coverage for PWID in 90 US metropolitan statistical areas (MSAs) during 1993-2007, a period in which, overall coverage did not change. METHODS:Drug treatment coverage was measured as the number of PWID in drug treatment, as calculated by treatment entry and census data, divided by numbers of PWID in each MSA. Variables suggested by the Theory of Community Action (i.e., need, resource availability, institutional opposition, organized support, and service symbiosis) were analyzed using mixed-effects multivariate models within dependent variables lagged in time to study predictors of later change in coverage. RESULTS:Mean coverage was low in 1993 (6.7%; SD 3.7), and did not increase by 2007 (6.4%; SD 4.5). Multivariate results indicate that increases in baseline unemployment rate (β = 0.312; pseudo-p < 0.0002) predict significantly higher treatment coverage; baseline poverty rate (β = - 0.486; pseudo-p < 0.0001), and baseline size of public health and social work workforce (β = 0.425; pseudo-p < 0.0001) were predictors of later mean coverage levels, and baseline HIV prevalence among PWID predicted variation in treatment coverage trajectories over time (baseline HIV * Time: β = 0.039; pseudo-p < 0.001). Finally, increases in black/white poverty disparity from baseline predicted significantly higher treatment coverage in MSAs (β = 1.269; pseudo-p < 0.0001). CONCLUSIONS:While harm reduction programs have historically been contested and difficult to implement in many US communities, and despite efforts to increase treatment coverage for PWID, coverage has not increased. Contrary to our hypothesis, epidemiologic need, seems not to be associated with change in treatment coverage over time. Resource availability and institutional opposition are important predictors of change over time in coverage. These findings suggest that new ways have to be found to increase drug treatment coverage in spite of economic changes and belt-tightening policy changes that will make this difficult.

Large-scale structural interventions and "Big Events" like revolutions, wars and major disasters can affect HIV transmission by changing the sizes of at-risk populations, making high-risk behaviors more or less likely, or changing contexts in which risk occurs. This paper describes new measures to investigate hypothesized pathways that could connect macro-social changes to subsequent HIV transmission. We developed a "menu" of novel scales and indexes on topics including norms about sex and drug injecting under different conditions, experiencing denial of dignity, agreement with cultural themes about what actions are needed for survival or resistance, solidarity and other issues. We interviewed 298 at-risk heterosexuals and 256 men who have sex with men in New York City about these measures and possible validators for them. Most measures showed evidence of criterion validity (absolute magnitude of Pearson's r ≥ 0.20) and reliability (Cronbach's alpha ≥ 0.70). These measures can be (cautiously) used to understand how macro-changes affect HIV and other risk. Many can also be used to understand risk contexts and dynamics in more normal situations. Additional efforts to improve and to replicate the validation of these measures should be conducted.

The opioid/overdose crisis in the United States and Canada has claimed hundreds of thousands of lives and has become a major field for research and interventions. It has embroiled pharmaceutical companies in lawsuits and possible bankruptcy filings. Effective interventions and policies toward this and future drug-related outbreaks may be improved by understanding the sociostructural roots of this outbreak. Much of the literature on roots of the opioid/overdose outbreak focuses on (1) the actions of pharmaceutical companies in inappropriately promoting the use of prescription opioids; (2) "deaths of despair" based on the deindustrialization of much of rural and urban Canada and the United States, and on the related marginalization and demoralization of those facing lifetimes of joblessness or precarious employment in poorly paid, often dangerous work; and (3) increase in occupationally-induced pain and injuries in the population. All three of these roots of the crisis-pharmaceutical misconduct and unethical marketing practices, despair based on deindustrialization and increased occupational pain-can be traced back, in part, to what has been called the "one-sided class war" that became prominent in the 1970s, became institutionalized as neo-liberalism in and since the 1980s, and may now be beginning to be challenged. We describe this one-sided class war, and how processes it sparked enabled pharmaceutical corporations in their misconduct, nurtured individualistic ideologies that fed into despair and drug use, weakened institutions that created social support in communities, and reduced barriers against injuries and other occupational pain at workplaces by reducing unionization, weakening surviving unions, and weakening the enforcement of rules about workplace safety and health. We then briefly discuss the implications of this analysis for programs and policies to mitigate or reverse the opioid/overdose outbreak.

Background: Increased drug use has disproportionately impacted rural areas across the U.S. People who use drugs are at risk of overdose and other medical complications, including infectious diseases. Understanding barriers to healthcare access for this often stigmatized population is key to reducing morbidity and mortality, particularly in rural settings where resources may be limited. Methods: We conducted 20 semi-structured interviews with people who use drugs, including 17 who inject drugs, in rural southern Illinois between June 2018 and February 2019. Interviews were analyzed using a modified grounded theory approach where themes are coded and organized as they emerge from the data. Results: Participants reported breaches of trust by healthcare providers, often involving law enforcement and Emergency Medical Services, that dissuaded them from accessing medical care. Participants described experiences of mistreatment in emergency departments, with one account of forced catheterization. They further recounted disclosures of protected health information by healthcare providers, including communicating drug test results to law enforcement and sharing details of counseling sessions with community members without consent. Participants also described a hesitancy common among people who use drugs to call emergency medical services for an overdose due to fear of arrest. Conclusion: Breaches of trust by healthcare providers in rural communities discouraged people who use drugs from accessing medical care until absolutely necessary, if at all. These experiences may worsen healthcare outcomes and further stigmatize this marginalized community. Structural changes including reforming and clarifying law enforcement's role in Emergency Departments as well as instituting diversion policies during arrests may help rebuild trust in these communities. Other possible areas for intervention include stigma training and harm reduction education for emergency medicine providers, as well as developing and implementing referral systems between Emergency Departments and local harm reduction providers and medically assisted drug treatment programs.

Russia has a widespread injection drug use epidemic with high prevalence of HIV and HCV among people who inject drugs (PWID). We conducted a mixed methods study of young (age 18-26) hard drug users in St. Petersburg. Thirty-nine structured and 10 semi-structured interviews were conducted. No HIV cases and two HCV cases were detected among the PWID subsample (n = 29). Amphetamine and other stimulants were common (70%), opioid use was rare and episodic. Consistent condom use was 10%. No PWID reported syringe-sharing, 51% reported other drug paraphernalia sharing. Most (89%) never or rarely communicated with older (30 +) opiate users. A new cohort of drug users in St. Petersburg may have emerged, which is much safer in its injection practices compared to previous cohorts. However, risky sexual practices among this new cohort may expose them to the possibility of sexual transmission of HIV and widespread drug paraphernalia sharing to the HCV epidemic.