Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

The making of community mental health policy in everyday street-level practice: An organizational ethnography

Scholars have used studies of “street-level organizations” to examine how policy is implemented, adapted, and changed through the practices of workers in real-world contexts. This dissertation follows in that tradition, tracing the ways in which Medicaid reforms work their way down to the street-level in a community mental health center with its origins in the clubhouse model of treatment. Based on twelve months of direct observation of street-level practices, interviews with workers, and analysis of agency documents and reports, I examine how new managerial reforms shape the strategies that workers use to provide access to community mental health services and to advance the clubhouse logic of recovery. These findings have implications for scholarship across the domains of community mental health practice, organizational studies, and policy research, suggesting the need for further investigation into how policy reform is produced through the everyday practices of street-level organizations. This dissertation uses organizational ethnographic methods to study workers’ practices at Community Club, a community mental health center located in Chicago, Illinois. The clubhouse is based on the idea that individuals whose lives have been adversely affected by severe mental illness can benefit from treatment in a setting that functions as a social club, where members experience themselves as valued and needed. At the same time, community mental health reforms have been advanced largely by new managerial arrangements that emphasize accountability and performance measurement. These reforms in governance and management produced considerable uncertainty for workers in how Community Club would adapt to changes in policy. This site provides an opportunity to examine how reforms “worked” in this particular setting and what became of the clubhouse model under new managerial arrangements. Data were collected from November 2009 until November 2010. I directly observed therapeutic interactions at Community Club and attended weekly team and managers meetings. Interviews were recorded with frontline workers, team leaders, and program administrators as questions emerged from my day-to-day observations of direct practices. I had access to multiple sources of organizational documentation, including corrective actions, internal notices, and training materials. I attended meetings, webinars, and teleconferences at the Illinois Division of Mental Health for a year. I also attended monthly meetings at the largest community behavioral health trade association in Illinois for two years. Interviews were conducted with key informants at the state and trade levels to better understand how community mental health policy reforms took shape in Illinois. Data were analyzed in an ongoing and iterative fashion for thematic connections. Multiple data sources allowed for triangulation and fact-checking as hypotheses emerged over the course of this study. This study finds that workers adjusted to reforms in governance and management in ways that were not reducible to formal statutes alone. First, new managerial reforms restructured the tensions that played out at the street-level as workers negotiated the competing demands of access to care. This study suggests that reforms may place pressure on workers to limit flexibility and openness, may produce both direct and indirect forms of rationing, and may introduce barriers that unevenly affect individuals who are “harder to serve.” Second, reforms in governance and management restructured three key logics of the clubhouse. Street-level practices that advanced community participation, informal group arrangements, and client self-determination were reshaped by organizational incentives and penalties that increased the costs for workers of providing these services. These changes had observable implications for individuals’ access to services and for workers’ ability to act in consonance with manifest principles of the clubhouse and recovery models of treatment. This dissertation supports the assertion that formal policy is changed through its implementation in real-world contexts of practice. By revealing the structures that shape most decisively what policy becomes in practice, this study enhances the visibility of social welfare reforms that may otherwise obfuscate how reforms “work” in practice. This study suggests that social policies should focus not only on accountability and performance measurement, but also on supplying workers with adequate resources to do their jobs well. If, as advocates and researchers have long suggested, there remains significant need for services that support social connection among people with severe mental illness, then it is important for scholars and policymakers to think about how to better equip organizations with the resources they need to facilitate this dimension of care. This dissertation is based on a single case study, which limits the generalizability of its findings. Street-level organizational studies build validity over multiple iterations of case selection, using a comparative perspective to distinguish particular from systematic features of organizational practice. More studies are needed that examine how community mental health policies are produced in the everyday life of organizations, in order to better understand how polices give shape to the nature and distribution of care

Search committee diversity and applicant pool representation of women and underrepresented minorities : a quasi-experimental field study

The diversification of applicant pools constitutes an important step for broadening the participation of women and underrepresented minorities (URMs) in the workforce. The current study focuses on recruiting diverse applicant pools in an academic setting. We test strategies grounded in homophily theory to attract a diverse set of applicants for open faculty positions. Analysis of recruitment data (13,750 job applications) showed that women search committee chairs and greater percentages of women on search committees related to more women applicants and that URMs search chairs and a greater percentage of URM members on search committees related to more URM applicants, resulting in 23% more women applicant pools with a woman chair and over 100% more URM applicants for a URM chair. Furthermore, women and URMs actively engage in ways to reach out to a more diverse set of applicants, whereas men and non-URMs’ behavior maintains the status quo. We discuss the implications and advancement of homophily theory that can ultimately increase the representation of women and URM in the workforce

Co-production of Public Services:Institutional Barriers to the Involvement of Citizens in Policy Implementation

Co-production refers to the involvement of citizens/service users in the direct implementation of policy. In practice, this means that public servants and citizens act jointly to deliver public services that would traditionally be the domain of the public servant alone. Co-production is increasingly posited as a desirable model of implementation for health and social policies, development and environment programs, and community safety, among other areas. However, while we have some understanding about the role of context in shaping approaches to policy implementation generally, comparatively less attention has been paid to the contextual contingency of co-production. This chapter employs an institutional logics framework to consider the different ways in which co-production plays a role - or not - in policy implementation. In particular, I discuss the way that a community logic, professional logic, market logic, and state logic in different sectors and different contexts shape public servants’ perceptions of their role visà- vis citizens in policy implementation and produce opportunities and barriers for co-production with citizens.</p