Experience of irreproducibility as a risk factor for poor mental health in biomedical science doctoral students: A survey and interview-based study.

High rates of irreproducibility and of poor mental health in graduate students have been reported in the biomedical sciences in the past ten years, but to date, little research has investigated whether these two trends interact. In this study, we ask whether the experience of failing to replicate an expected finding impacts graduate students' mental health. Using an online survey paired with semi-structured qualitative interviews, we examined how often biomedical science doctoral students at a large American public university experienced events that could be interpreted as failures to replicate and how they responded to these experiences. We found that almost all participants had experience with irreproducibility: 84% had failed to replicate their own results, 70% had failed to replicate a colleague's finding, and 58% had failed to replicate a result from the published literature. Participants reported feelings of self-doubt, frustration, and depression while experiencing irreproducibility, and in 24% of cases, these emotional responses were strong enough to interfere with participants' eating, sleeping, or ability to work. A majority (82%) of participants initially believed that the anomalous results could be attributed to their own error. However, after further experimentation, most participants concluded that the original result was wrong (38%), that there was a key difference between the original experiment and their own (17%), or that there was a problem with the protocol (17%). These results suggest that biomedical science graduate students may be biased towards initially interpreting failures to replicate as indicative of a lack of skill, which may trigger or perpetuate feelings of anxiety, depression, or impostorism.

Mapping the discursive dimensions of the reproducibility crisis: A mixed methods analysis.

To those involved in discussions about rigor, reproducibility, and replication in science, conversation about the "reproducibility crisis" appear ill-structured. Seemingly very different issues concerning the purity of reagents, accessibility of computational code, or misaligned incentives in academic research writ large are all collected up under this label. Prior work has attempted to address this problem by creating analytical definitions of reproducibility. We take a novel empirical, mixed methods approach to understanding variation in reproducibility discussions, using a combination of grounded theory and correspondence analysis to examine how a variety of authors narrate the story of the reproducibility crisis. Contrary to expectations, this analysis demonstrates that there is a clear thematic core to reproducibility discussions, centered on the incentive structure of science, the transparency of methods and data, and the need to reform academic publishing. However, we also identify three clusters of discussion that are distinct from the main body of articles: one focused on reagents, another on statistical methods, and a final cluster focused on the heterogeneity of the natural world. Although there are discursive differences between scientific and popular articles, we find no strong differences in how scientists and journalists write about the reproducibility crisis. Our findings demonstrate the value of using qualitative methods to identify the bounds and features of reproducibility discourse, and identify distinct vocabularies and constituencies that reformers should engage with to promote change.

Developing a Collaborative Agenda for Humanities and Social Scientific Research on Laboratory Animal Science and Welfare.

Improving laboratory animal science and welfare requires both new scientific research and insights from research in the humanities and social sciences. Whilst scientific research provides evidence to replace, reduce and refine procedures involving laboratory animals (the '3Rs'), work in the humanities and social sciences can help understand the social, economic and cultural processes that enhance or impede humane ways of knowing and working with laboratory animals. However, communication across these disciplinary perspectives is currently limited, and they design research programmes, generate results, engage users, and seek to influence policy in different ways. To facilitate dialogue and future research at this interface, we convened an interdisciplinary group of 45 life scientists, social scientists, humanities scholars, non-governmental organisations and policy-makers to generate a collaborative research agenda. This drew on methods employed by other agenda-setting exercises in science policy, using a collaborative and deliberative approach for the identification of research priorities. Participants were recruited from across the community, invited to submit research questions and vote on their priorities. They then met at an interactive workshop in the UK, discussed all 136 questions submitted, and collectively defined the 30 most important issues for the group. The output is a collaborative future agenda for research in the humanities and social sciences on laboratory animal science and welfare. The questions indicate a demand for new research in the humanities and social sciences to inform emerging discussions and priorities on the governance and practice of laboratory animal research, including on issues around: international harmonisation, openness and public engagement, 'cultures of care', harm-benefit analysis and the future of the 3Rs. The process outlined below underlines the value of interdisciplinary exchange for improving communication across different research cultures and identifies ways of enhancing the effectiveness of future research at the interface between the humanities, social sciences, science and science policy.

"Triple negative breast cancer": Translational research and the (re)assembling of diseases in post-genomic medicine.

The paper examines the debate about the nature and status of "Triple-negative breast cancer", a controversial biomedical entity whose existence illustrates a number of features of post-genomic translational research. The emergence of TNBC is intimately linked to the rise of molecular oncology, and, more generally, to the changing configuration of the life sciences at the turn of the new century. An unprecedented degree of integration of biological and clinical practices has led to the proliferation of bio-clinical entities emerging from translational research. These translations take place between platforms rather than between clinical and laboratory settings. The complexity and heterogeneity of TNBC, its epistemic and technical, biological and clinical dualities, result from its multiple instantiations via different platforms, and from the uneven distribution of biological materials, techniques, and objects across clinical research settings. The fact that TNBC comes in multiple forms, some of which seem to be incompatible or, at least, only partially overlapping, appears to be less a threat to the whole endeavor, than an aspect of an ongoing translational research project. Discussions of translational research that rest on a distinction between basic research and its applications fail to capture the dynamics of this new domain of activity, insofar as application is built-in from the very beginning in the bio-clinical entities that emerge from the translational research domain.

A Knockout Experiment: Disciplinary Divides and Experimental Skill in Animal Behaviour Genetics.

In the early 1990s, a set of new techniques for manipulating mouse DNA allowed researchers to 'knock out' specific genes and observe the effects of removing them on a live mouse. In animal behaviour genetics, questions about how to deploy these techniques to study the molecular basis of behaviour became quite controversial, with a number of key methodological issues dissecting the interdisciplinary research field along disciplinary lines. This paper examines debates that took place during the 1990s between a predominately North American group of molecular biologists and animal behaviourists around how to design, conduct, and interpret behavioural knockout experiments. Drawing from and extending Harry Collins's work on how research communities negotiate what counts as a 'well-done experiment,' I argue that the positions practitioners took on questions of experimental skill reflected not only the experimental traditions they were trained in but also their differing ontological and epistemological commitments. Different assumptions about the nature of gene action, eg., were tied to different positions in the knockout mouse debates on how to implement experimental controls. I conclude by showing that examining representations of skill in the context of a community's knowledge commitments sheds light on some of the contradictory ways in which contemporary animal behaviour geneticists talk about their own laboratory work as a highly skilled endeavour that also could be mechanised, as easy to perform and yet difficult to perform well.

Making organisms model human behavior: situated models in North-American alcohol research, since 1950.

We examine the criteria used to validate the use of nonhuman organisms in North-American alcohol addiction research from the 1950s to the present day. We argue that this field, where the similarities between behaviors in humans and non-humans are particularly difficult to assess, has addressed questions of model validity by transforming the situatedness of non-human organisms into an experimental tool. We demonstrate that model validity does not hinge on the standardization of one type of organism in isolation, as often the case with genetic model organisms. Rather, organisms are viewed as necessarily situated: they cannot be understood as a model for human behavior in isolation from their environmental conditions. Hence the environment itself is standardized as part of the modeling process; and model validity is assessed with reference to the environmental conditions under which organisms are studied.

Testing devices or experimental systems? Cancer clinical trials take the genomic turn.

Clinical trials are often described as machine-like systems for generating specific information concerning drug safety and efficacy, and are understood as a component of the industrial drug development processes. This paper argues that contemporary clinical trials in oncology are not reducible to mere drug testing. Drawing on ethnographic fieldwork and interviews with researchers in the field of oncology from 2010 to 2013, we introduce a conceptual contrast between trials as testing machines and trials as clinical experimental systems to draw attention to the ways trials are increasingly being used to ask open-ended scientific questions. When viewed as testing machines, clinical trials are seen as a means to produce answers to straightforward questions and deviations from the protocol are seen as bugs in the system; but practitioners can also treat trials as clinical experimental systems to investigate as yet undefined problems and where heterogeneity becomes a means to produce novel biological or clinical insights. The rise of "biomarker-driven" clinical trials in oncology, which link measurable biological characteristics such as genetic mutations to clinical features such as a patient's response to a particular drug, exemplifies a trend towards more experimental styles of clinical work. These transformations are congruent with changes in the institutional structure of clinical research in oncology, including a movement towards more flexible, networked research arrangements, and towards using individual patients as model systems for asking biological questions.

Therapy's Shadow: A Short History of the Study of Resistance to Cancer Chemotherapy.

This article traces the history of research on resistance to drug therapy in oncology using scientometric techniques and qualitative analysis. Using co-citation analysis, we generate maps to visualize subdomains in resistance research in two time periods, 1975-1990 and 1995-2010. These maps reveal two historical trends in resistance research: first, a shift in focus from generic mechanisms of resistance to chemotherapy to a focus on resistance to targeted therapies and molecular mechanisms of oncogenesis; and second, a movement away from an almost exclusive reliance on animal and cell models and toward the generation of knowledge about resistance through clinical trial work. A close reading of highly cited articles within each subdomain cluster reveals specific points of transition from one regime to the other, in particular the failure of several promising theories of resistance to be translated into clinical insights and the emergence of interest in resistance to a new generation of targeted agents such as imatinib and trastuzumab. We argue that the study of resistance in the oncology field has thus become more integrated with research into cancer therapy - rather than constituting it as a separate domain of study, as it has done in the past, contemporary research treats resistance as the flip side to treatment, as therapy's shadow.