On Partial Identification of the Pure Direct Effect

In causal mediation analysis, nonparametric identification of the pure (natural) direct effect typically relies on, in addition to no unobserved pre-exposure confounding, fundamental assumptions of (i) so-called "cross-world-counterfactuals" independence and (ii) no exposure- induced confounding. When the mediator is binary, bounds for partial identification have been given when neither assumption is made, or alternatively when assuming only (ii). We extend existing bounds to the case of a polytomous mediator, and provide bounds for the case assuming only (i). We apply these bounds to data from the Harvard PEPFAR program in Nigeria, where we evaluate the extent to which the effects of antiretroviral therapy on virological failure are mediated by a patient's adherence, and show that inference on this effect is somewhat sensitive to model assumptions.Comment: 24 pages, 4 figure

Semiparametric Methods for Causal Mediation Analysis and Measurement Error

Chapter 1: Since the early 2000s, evidence has accumulated for a significant differential effect of first-line antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV) treatment outcomes, such as CD4 response and viral load suppression. This finding was replicated in our data from the Harvard President's Emergency Plan for AIDS Relief (PEPFAR) program in Nigeria. Investigators were interested in finding the source of these differences, i.e., understanding the mechanisms through which one regimen outperforms another, particularly via adherence. This amounts to a mediation question with adherence playing the role of mediator. Existing mediation analysis results, however, have relied on an assumption of no exposure-induced confounding of the intermediate variable, and generally require an assumption of no unmeasured confounding for nonparametric identification. Both assumptions are violated by the presence of drug toxicity. In this paper, we relax these assumptions and show that certain path-specific effects remain identified under weaker conditions. We focus on the path-specific effect solely mediated by adherence and not by toxicity and propose a suite of estimators for this effect, including a semiparametric-efficient, multiply-robust estimator. We illustrate with simulations and present results from a study applying the methodology to the Harvard PEPFAR data. Chapter 2: In causal mediation analysis, nonparametric identification of the pure (natural) direct effect typically relies on fundamental assumptions of (i) so-called ``cross-world-counterfactuals" independence and (ii) no exposure-induced confounding. When the mediator is binary, bounds for partial identification have been given when neither assumption is made, or alternatively when assuming only (ii). We extend these bounds to the case of a polytomous mediator, and provide bounds for the case assuming only (i). We apply these bounds to data from the Harvard PEPFAR program in Nigeria, where we evaluate the extent to which the effects of antiretroviral therapy on virological failure are mediated by a patient's adherence, and show that inference on this effect is somewhat sensitive to model assumptions. Chapter 3: When assessing the presence of an exposure causal effect on a given outcome, it is well known that classical measurement error of the exposure can seriously reduce the power of a test of the null hypothesis in question, although its type I error rate will generally remain controlled at the nominal level. In contrast, classical measurement error of a confounder can have disastrous consequences on the type I error rate of a test of treatment effect. In this paper, we develop a large class of semiparametric test statistics of an exposure causal effect, which are completely robust to classical measurement error of a subset of confounders. A unique and appealing feature of our proposed methods is that they require no external information such as validation data or replicates of error-prone confounders. The approach relies on the observation that under the sharp null hypothesis of no exposure causal effect, the standard assumption of no unmeasured confounding implies that the outcome is in fact a valid instrumental variable for the association between the error-prone confounder and the exposure. We present a doubly-robust form of this test that requires only one of two models -- an outcome-regression and a propensity-score model -- to be correctly specified for the resulting test statistic to have correct type I error rate. Validity and power within our class of test statistics is demonstrated via multiple simulation studies. We apply the methods to a multi-U.S.-city, time-series data set to test for an effect of temperature on mortality while adjusting for atmospheric particulate matter with diameter of 2.5 micrometres or less (PM2.5), which is well known to be measured with error.Biostatistic

Radical Surgery in the Treatment of Localized Carcinoma of the Prostate

New methods of early detection combined with recent advances in surgical techniques have resulted in more patients undergoing radical surgery for treatment of localized carcinoma of the prostate. Over 350 radical prostatectomies have been performed by our group since January 1987. We review the role of radical prostatectomy in the treatment of prostate cancer and our experience with 100 patients undergoing radical retropubic prostatectomy since the advent of nerve-sparing techniques to preserve potency

HIV Prevention and Care Among Black Cisgender Sexual Minority Men and Transgender Women: Protocol for an HIV Status–Neutral Cohort Study Using an Observational-Implementation Hybrid Approach

Background: Black cisgender gay, bisexual, and other sexual minority men (SMM) and transgender women (TW) continue to be heavily affected by HIV. Further research is needed to better understand HIV prevention and care outcomes in this population. In particular, there is a need for research examining the impact of substance use and sleep health on HIV prevention and treatment outcomes among Black SMM and TW. Objective: This paper outlines the study methods being used in the recently launched follow-up study to the Neighborhoods and Networks (N2) study, which we refer to as N2 Part 2 (N2P2). N2P2 aims to address this gap in the literature, build off the findings of the original N2 study, and identify socioenvironmental determinants of health, including whether neighborhood and network factors mediate and moderate these relationships. Methods: Building on the N2 cohort study in Chicago from 2018 to 2022, N2P2 used a prospective longitudinal cohort design and an observational-implementation hybrid approach. With sustained high levels of community engagement, we aim to recruit a new sample of 600 Black SMM and TW participants residing in the Chicago metropolitan statistical area. Participants are asked to participate in 3 study visits across an 18-month study period (1 visit every 9 months). Four different forms of data are collected per wave: (1) an in-person survey, (2) biological specimen collection, (3) a daily remote ecological momentary assessment for 14 days after each study visit, and (4) data from electronic health records. These forms of data collection continue to assess neighborhood and network factors and specifically explore substance use, sleep, immune function, obesity, and the implementation of potential interventions that address relevant constructs (eg, alcohol use and pre-exposure prophylaxis adherence). Results: The N2P2 study was funded in August 2021 by the National Institute of Drug Abuse (R01DA054553 and R21DA053156) and National Heart, Lung, and Blood Institute (R01HL160325). This study was launched in November 2022. Recruitment and enrollment for the first wave of data collection are currently ongoing. Conclusions: The N2P2 study is applying innovative methods to comprehensively explore the impacts of substance use and sleep health on HIV-related outcomes among an HIV status-neutral cohort of Black SMM and TW in Chicago. This study is applying an observational-implementation hybrid design to help us achieve findings that support rapid translation, a critical priority among populations such as Black SMM and TW that experience long-standing inequities with regard to HIV and other health-related outcomes. N2P2 will directly build off the findings that have resulted from the original N2 study among Black SMM and TW in Chicago. These findings provide a better understanding of multilevel (eg, individual, network, and neighborhood) factors that contribute to HIV-related outcomes and viral suppression among Black SMM and TW. International registered report identifier (irrid): DERR1-10.2196/48548.</p

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

Projects in Applied Data Science: Fall 2019

This document contains semester projects for students in CSCI 4381/7000 Data ScienceProjects. This course explores concepts and techniques for design, formulation and execution ofpractical, applied data science. Topics covered include experimental design, statistical analysisand predictive modeling, machine learning, data visualization, scientific writing and presentation.During the class, students selected a semester-long project to acquire, analyze, and understanddata in support of a research question. In addition to traditional lectures, students read anddiscussed published papers on data science topics, practiced skills in recitation sessions, andentertained guest lectures from expert data scientists in the field. Outside of these readings andrecitations, students were allowed to work on their projects exclusively and were supported withmeetings, peer-discussion and copyediting. In terms of the scope of the final product, undergraduate students were asked to perform aresearch or engineering task of some complexity while graduate students were additionallyrequired to perform a survey of related work, demonstrate some novelty in their approach, anddescribe the position of their contribution within the broader literature. All students whoperformed at or above these expectations were offered the opportunity to contribute their paperfor publication in this technical summary. The diversity of the papers herein is representative of the diversity of interests of the students inthe class. There is no common trend among the papers submitted and each takes a differenttopic to task. Students made use of open data or worked with organizations to acquire data.Several students pivoted their projects early on due to limitations and difficulties in data access--- a real-world challenge in practical data science. The projects herein range from analyzingtraffic in cities, restaurant trends and Facebook responses to smartphone accelerometer data,scaling laws in higher education, and bicycle trends in Boulder, Colorado. Analysis approachesare similarly varied: visualization, statistical analysis and modeling, machine learning,reinforcement learning, etc.. Most papers can be understood as exploratory data analysis,although some emphasize interactive visualization and others emphasize statistical modelingand prediction aimed at testing a well-defined research question. To inform the style of theirapproach, students read papers from a broad sampling of original research. They used thesereadings to build an understanding of approaches to presentation and analysis in the modernscientific literature. One paper was held out from this compendium so that it could be submittedfor publication to a peer-reviewed venue. Please direct questions/comments on individual papers to the student authors when contactinformation has been made available.</p

Resource bricolage and growth of product and market scope in social enterprises

This research aims to understand how resource bricolage strategy plays a role in the growth of social enterprises in terms of their product and market. Based on interviews with nine social enterprises, our exploratory finding suggests that social enterprises often employ both internal and network resources in the process of making do. We further explore the relationship between the form of resource utilisation and the nature and scope of activities that the social enterprises embark upon, and find that only those relying on both internal and network bricolage are able to expand into new markets utilising newly developed products. We also find that social enterprises relying on only internal resources can reach the same point through incremental improvisation, by first moving towards either product extension or market expansion, before then embarking on the other. This research contributes to the social entrepreneurship literature by enhancing our understanding of the relationship between resource bricolage strategy and growth of social enterprises through product/ market scope in a penurious environment. The findings of this research also have implications for social enterprise managers and policy makers in utilising their resources and responding to environmental opportunities and challenges

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead