Conservatism Gets Funded? A Field Experiment on the Role of Negative Information in Novel Project Evaluation.

The evaluation and selection of novel projects lies at the heart of scientific and technological innovation, and yet there are persistent concerns about bias, such as conservatism. This paper investigates the role that the format of evaluation, specifically information sharing among expert evaluators, plays in generating conservative decisions. We executed two field experiments in two separate grant-funding opportunities at a leading research university, mobilizing 369 evaluators from seven universities to evaluate 97 projects, resulting in 761 proposal-evaluation pairs and more than $250,000 in awards. We exogenously varied the relative valence (positive and negative) of others' scores and measured how exposures to higher and lower scores affect the focal evaluator's propensity to change their initial score. We found causal evidence of a negativity bias, where evaluators lower their scores by more points after seeing scores more critical than their own rather than raise them after seeing more favorable scores. Qualitative coding of the evaluators' justifications for score changes reveals that exposures to lower scores were associated with greater attention to uncovering weaknesses, whereas exposures to neutral or higher scores were associated with increased emphasis on nonevaluation criteria, such as confidence in one's judgment. The greater power of negative information suggests that information sharing among expert evaluators can lead to more conservative allocation decisions that favor protecting against failure rather than maximizing success.

The CTSA External Reviewer Exchange Consortium (CEREC): Engagement and efficacy.

INTRODUCTION: Many institutions evaluate applications for local seed funding by recruiting peer reviewers from their own institutional community. Smaller institutions, however, often face difficulty locating qualified local reviewers who are not in conflict with the proposal. As a larger pool of reviewers may be accessed through a cross-institutional collaborative process, nine Clinical and Translational Science Award (CTSA) hubs formed a consortium in 2016 to facilitate reviewer exchanges. Data were collected to evaluate the feasibility and preliminary efficacy of the consortium. METHODS: The CTSA External Reviewer Exchange Consortium (CEREC) has been supported by a custom-built web-based application that facilitates the process and tracks the efficiency and productivity of the exchange. RESULTS: All nine of the original CEREC members remain actively engaged in the exchange. Between January 2017 and May 2019, CEREC supported the review process for 23 individual calls for proposals. Out of the 412 reviews requested, 368 were received, for a fulfillment ratio of 89.3%. The yield on reviewer invitations has remained consistently high, with approximately one-third of invitations being accepted, and of the reviewers who agreed to provide a review, 88.3% submitted a complete review. Surveys of reviewers and pilot program administrators indicate high satisfaction with the process. CONCLUSIONS: These data indicate that a reviewer exchange consortium is feasible, adds value to participating partners, and is sustainable over time.

The Open Translational Science in Schizophrenia (OPTICS) project: an open-science project bringing together Janssen clinical trial and NIMH data.

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia. The project aims were to show the value of using shared data to examine: therapeutic safety and efficacy; disease etiologies and course; and methods development. The success of project investigators was due to collaboration from project applications through analyses, with support from the Harvard Catalyst. Project work was independent of Janssen; all intellectual property was dedicated to the public. Efforts such as this are necessary to gain deeper insights into the biology of disease, foster collaboration, and to achieve the goal of developing better treatments, reducing the overall public health burden of devastating brain diseases.

Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women.

Posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder with a particularly high burden for women. Emerging evidence suggests PTSD may be more heritable among women and evidence from animal models and human correlational studies suggest connections between sex-linked biology and PTSD vulnerability, which may extend to the disorder's genetic architecture. We conducted a genome-wide association study (GWAS) of PTSD in a primarily African American sample of women from the Detroit Neighborhood Health Study (DNHS) and tested for replication in an independent cohort of primarily European American women from the Nurses Health Study II (NHSII). We genotyped 413 DNHS women - 94 PTSD cases and 319 controls exposed to at least one traumatic event - on the Illumina HumanOmniExpress BeadChip for >700,000 markers and tested 578 PTSD cases and 1963 controls from NHSII for replication. We performed a network-based analysis integrating data from GWAS-derived independent regions of association and the Reactome database of functional interactions. We found genome-wide significant association for one marker mapping to a novel RNA gene, lincRNA AC068718.1, for which we found suggestive evidence of replication in NHSII. Our network-based analysis indicates that our top GWAS results were enriched for pathways related to telomere maintenance and immune function. Our findings implicate a novel RNA gene, lincRNA AC068718.1, as risk factor for PTSD in women and add to emerging evidence that non-coding RNA genes may play a crucial role in shaping the landscape of gene regulation with putative pathological effects that lead to phenotypic differences.

Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger.

Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to isoproterenol in adult rat ventricular myocytes. Responses to isoproterenol were largely mediated through the beta1AR in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the isoproterenol concentration-response curve. Responses to isoproterenol could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling. Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that beta2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart.

Polymorphisms in DNA double-strand break repair genes and breast cancer risk in the Nurses' Health Study.

Genetic polymorphisms in double-strand break repair genes may influence DNA repair capacity and, in turn, confer predisposition to breast cancer. We prospectively assessed the associations of candidate polymorphisms G31479A (R188H) in XRCC2, A4541G (5'-UTR), A17893G (IVS5-14) and C18067T (T241 M) in XRCC3, and C299T (5'-UTR) and T1977C (D501D) in Ligase IV with breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n=1004; controls, n=1385). We observed no overall associations of these six genotypes with breast cancer risk. Four common haplotypes in XRCC3 accounted for 99% of the chromosomes of the present study population. We observed that Ligase IV 1977C carriers were at increased breast cancer risk if they had a first degree family history of breast cancer (test for interaction, P=0.01). We observed that the XRCC2 R188H polymorphism modified the association of plasma alpha-carotene level and breast cancer risk (test for ordinal interaction, P=0.03); the significantly decreased risk seen overall for women in the highest quartile of plasma alpha-carotene was only present among 188H non-carriers (the top quartile versus the bottom quartile; multivariate odds ratio, 0.55; 95% confidence interval, 0.40-0.75). No significant interactions were seen between any of these polymorphisms and duration or dose of cigarette smoking. The gene-environment interaction data suggest that the subtle effects of some of these variants on breast cancer risk may be magnified in the presence of certain exposures.

Effects of Na(+)/Ca(2+)-exchanger overexpression on excitation-contraction coupling in adult rabbit ventricular myocytes.

The Na(+)/Ca(2+)-exchanger (NCX) is the main mechanism by which Ca(2+) is transported out of the ventricular myocyte. NCX levels are raised in failing human heart, and the consequences of this for excitation-contraction coupling are still debated. We have increased NCX levels in adult rabbit myocytes by adenovirally-mediated gene transfer and examined the effects on excitation-contraction coupling after 24 and 48 h. Infected myocytes were identified through expression of green fluorescent protein (GFP), transfected under a separate promoter on the same viral construct. Control experiments were done with both non-infected myocytes and those infected with adenovirus expressing GFP only. Contraction amplitude was markedly reduced in NCX-overexpressing myocytes at either time point, and neither increasing frequency nor raising extracellular Ca(2+) could reverse this depression. Resting membrane potential and action potential duration were largely unaffected by NCX overexpression, as was peak Ca(2+) entry via the L-type Ca(2+) channel. Systolic and diastolic Ca(2+) levels were significantly reduced, with peak systolic Ca(2+) in NCX-overexpressing myocytes lower than diastolic levels in control cells at 2 m m extracellular Ca(2+). Both cell relengthening and the decay of the Ca(2+) transient were significantly slowed. Sarcoplasmic reticulum (SR) Ca(2+) stores were completely depleted in a majority of myocytes, and remained so despite increasingly vigorous loading protocols. Depressed contractility following NCX overexpression is therefore related to decreased SR Ca(2+) stores and low diastolic Ca(2+) levels rather than reduced Ca(2+) entry.