Research Ethics and Integrity (RE and I)

1. Research Ethics and Integrity (RE and I) Professor K T Wann Former Deputy Dean of the University Graduate College Honorary Professor of Cell Physiology School of Pharmacy and Pharmaceutical Sciences Cardiff University Wales, UK

2. Research Ethics and Integrity (the context) Research is much more in the headlines We are all subject to the “Impact” driver and we feel that it has become “essential” to publish andpublicisepositive, potentially important results (read worthwhile or immense benefits) Negative data or research dead ends (cul de sacs) are not desirable outcomes So the tendency is to ignore (or at least not highlight) negative outcomes and to embellish / elaborate positive data Accentuate the positive, eliminate the negative We need to focus on effects on human behaviour

3. Questions around RE and I The first considerations: the what, who, why and how? What do we mean by research ethics and integrity? Who are we directing this conversation to? (responsibility) Why work ethically or with integrity? What are the challenges / obstacles? Are there pressures not to comply? What measures are in place to deal with unethical practices? What are the consequences of working unethically? How do we “train” ourselves to conduct ourselves ethically and with integrity? (deal with human emotions)

4. Research Ethics and Integrity • Research Misconduct (RM) • Publication ethics (PE)

5. Research Ethics and Integrity Sources of information https://www.sciencemag.org/news/2012/09/harvard-psychology-researcher-committed-fraud-us-investigation-concludes https://www.apa.org/monitor/2014/01/research-misconduct https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720946/ https://en.wikipedia.org/wiki/List_of_scientific_misconduct_incidents https://publicationethics.org/ http://satoriproject.eu/

6. http://ccnmtl.columbia.edu/projects/rcr/

7. https://ori.hhs.gov/TheLab/

8. Research Integrity is important for the Institution (CU) • Compliance, good research conduct and personal responsibility. • The primary responsibility for safeguarding the integrity of any research undertaken lies with the individual researcher.

9. CU Research Integrity and Governance Code of Practice • Principles • Excellence • Honesty • Openness • Rigour Accountability • Care & Respect • Commitments • Leadership & Supervision • Research Data • Publications & Authorship • Training • Ethical requirements • Intellectual Property

10. The landscape • The team leader is the guilty party (big high profile cases) • The deliberate act of an individual in a team • What many cases have in common is that the rules are known but there is still a belief that nothing wrong has been done

11. Personal experience • Fabrication of qualifications in grant application • Fabrication of a CV – publication list • Fabrication of key data in a PhD Thesis • These cases illustrated to me a clear breaking of known rules, a belief that nothing wrong has been done and a certain condoning by the community

12. Some examples of research misconduct • Misrepresentation of data (a slippery slope) • Fabrication or fudging of data (n numbers etc) • Plagiarism (willful or unintentional) • Substitution in written exams • Purchasing a PhD Thesis • Author order in publications • Undeclared conflict of interest • Flawed peer review • Publication duplication practice • Valid citation practices • Lack of informed consent • Lack of ethical / home office approval

13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720946/

14. Some examples of misconduct • The misrepresentation or data (a slippery slope) • The fabrication or fudging of data (n numbers etc) • The belief is that doing this does not alter the main message or conclusions

15. Working ethically Personal integrity and honesty Ethical procedures or rules: Working ethically with animals Working ethically with humans (informed consent, privacy, sensitivity etc)

16. CASE 1 Penelope Brighton is a second year graduate student in Dr. David Gilligan's cell biology lab. Gilligan is a highly productive, well-published, respected investigator whose students receive prestigious post-docs. As part of Brighton's thesis, she has begun to characterize the localization of a newly discovered protein within cells. In her first, quick experiments, Brighton found some potentially interesting results. Gilligan is quite excited about Brighton's project and is in the process of writing a grant using Brighton's results as preliminary data. https://www.onlineethics.org/Resources/gradres/gradresv5/data.aspx

17. CASE 1 cont. Brighton followed up the initial experiments by performing in-depth, well-controlled experiments. She changed several experimental conditions. She used immunopurified antibodies instead of crude antisera and changed blocking conditions to eliminate staining by preimmune sera. As Brighton sat by the microscope collecting data, she was surprised to find that her protein was present in all of the cells, but that it was not localized where she or Gilligan expected it to be. As she scanned several slides, she could find only two cells out of hundreds where the protein appeared to localize where they had hypothesized it would. In all of the other cells, the staining was in a different, specific area. Brighton believed the new staining to be clean and consistent, but the staining does not look like the initial results with crude sera. Brighton realized that the characterization of the protein may not be as straightforward as originally expected. Brighton attempted to discuss her new results with Gilligan. However, Gilligan did not seem interested in all of the data. He said that they would deal with the staining details later, but that they need to get the grant application out now. Gilligan asked Brighton to create a figure for the grant using one of the cells where the localization fit with the proposed hypothesis. In the grant application, Gilligan did not mention that the figure is an example of an atypical result. Instead, he suggested that all of the data from these experiments completely support the hypothesis.

18. CASE 1 cont Brighton read a draft of the grant and was shocked by the spin Gilligan had put on the data. When discussing the draft with Gilligan, she stressed that most of the localization data did not agree with the hypothesis. Gilligan insisted that the figure in the grant certainly supports the hypothesis. He said that the standards for presenting data as preliminary results in a grant application are not as stringent as those for publishing data in a journal article. Gilligan stated that it is better to present the data his way. Mentioning the unexpected results would only create doubt among the grant reviewers and decrease the likelihood of funding for the project.

19. CASE 1 cont. • Discussion questions • If the definition of scientific misconduct is fabrication, falsification, plagiarism, deception or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting or reporting research, did Gilligan represent his laboratory's work appropriately to the funding agency? Or is he guilty of scientific misconduct? • Would the situation be different if the research were being presented in another format? • How well-supported must a result be before it is presented at a seminar at another university? in a meeting abstract? in a progress report for the department? in a published paper?

20. CASE 1 cont. • Discussion questions • What possible actions are available to Brighton and other graduate students who feel their work is being misrepresented? • Should Brighton take action? If so, what would be an appropriate form of action? • As a thesis adviser, what are Gilligan's obligations toward Brighton? In this case, is Gilligan fulfilling his obligations as a thesis adviser?

21. CASE 2 Nellie Shepherd is a graduate student at a large Midwestern university working with a group of graduate students and post-doctoral fellows in the lab of Dr. Thomas Katz. The primary focus of the lab group's research is various aspects of the fate, transport and biological effects of 1,3,5-trimethyltriazinetrione (TTT) in aquatic systems. TTT is a by-product of several chemical manufacturing processes and is extremely difficult to remove from wastewater. Katz, a well-established scientist, is internationally known for his work on TTT. Much of his current research is funded on an annual basis by a consortium of chemical companies that generate wastewater containing TTT. Katz has the highest funding level and best equipped laboratory in the department; however, his students find him distant and communication difficult. https://www.onlineethics.org/Resources/gradres/gradresv2/wrongtree.aspx#scen1

22. CASE 2 cont For her dissertation research, Nellie is attempting to determine what environmental factors have contributed to the decline of native fish species downstream from the point at which wastewater from several chemical companies is released into the Missouri River. In addition to TTT, the wastewater contains numerous other substances, including dipropyl phthalate (DPP). At present, no regulatory levels have been established for TTT or DPP; for a variety of reasons, there is much public interest in TTT whereas DPP has been largely ignored. In a field survey, Nellie found large differences between enzyme levels in fish collected upstream and downstream from the area where wastewater enters the river, with the lowest levels in fish collected closest to the source of wastewater. Short-term experiments conducted by Katz's lab several years earlier did not indicate that native fish species were adversely affected by exposure to TTT, although enzyme levels were not analyzed. An extensive literature search yielded a series of papers indicating that exposure to DPP decreased enzyme levels in several European fish species and linking low enzyme levels to increased susceptibility to disease. Nellie is concerned that DPP, rather than TTT, is the cause of the biochemical changes she has observed and designs a series of simple lab experiments to determine whether exposure to DPP decreases enzyme levels in native fish species.

23. CASE 2 cont Nellie arranges a meeting with Katz in which she summarizes the papers she has found showing effects of DPP similar to those she has observed. She also describes the experiments she feels are needed to determine if DPP decreases enzyme levels. Katz tells her that she is barking up the wrong tree and insists that she limit her research to the effects of TTT because that is what the lab's funding is designated for. Nellie is surprised by Katz's response to her proposed experiments. When she tries to pursue the issue, she is abruptly dismissed. Nellie discusses her meeting with Katz with several members of the lab group. Everyone she talks to feels that her concerns about DPP are valid. Several weeks later, one of the post- docs tells her that Katz confided in him that he didn't want Nellie to "open up another can of worms for the chemical industry. "Nellie knows that loss of the chemical industry funding would be devastating to the lab. She realizes that she can probably complete her dissertation without addressing DPP. However, if DPP has caused the decline of native fish species, this issue needs to be addressed quickly because several of the fish species are considered to be on the verge of extinction. Nellie has the materials and reagents she needs to conduct the experiments evaluating DPP.

24. CASE 2 cont • Discussion Questions • Should Nellie proceed with the experiments evaluating DPP? • What issues are involved in such a decision?

25. CASE 2 cont • Scenario 1 • Nellie decides to obey Katz's instructions. She does not include an evaluation of DPP in her work. She refocuses her dissertation topic, limiting it to the effects of exposure to TTT. Results of her work support the preliminary experiments and indicate that TTT has no major adverse effect on the fish species studied. Katz asks Nellie to include an evaluation of the effects of elevated water temperature on fish enzyme levels. Discharge of water used for cooling by an electrical power plant has caused a 3 C increase in the average annual water temperature of the Missouri River in Nellie's study area • . • Discussion Questions • Has Nellie compromised her integrity by omitting DPP from her research? • In what way is the analysis of this case changed by Katz's request that temperature be evaluated?

26. CASE 2 cont • Scenario 2 • Nellie proceeds with the experiments evaluating the effects of DPP on two fish species. Her results indicate that exposure to DPP results in decreased enzyme levels. • Now that she has the additional data, Nellie recalls Katz's irritation when she initially suggested evaluating DPP. Because of her apprehension, she decides not to tell Dr. Katz about these experiments and proceeds with her dissertation research as described in Scenario 1. • Discussion Questions • By conducting the experiments and not divulging the results, has Nellie compromised her integrity more than in Scenario 1? • Was she wrong to have conducted these experiments using resources obtained from chemical consortium funds earmarked for research on DPP?

27. CASE 2 cont • Scenario 3 • Nellie decides to tell Katz the results of the experiments with DPP. He becomes irritated when she admits that she has conducted the experiments, and he informs her that if she wishes to continue her investigation of DPP, she will need to find another source of funding and another laboratory to work in. • Discussion Questions • Is Katz's behavior appropriate? Note: The research of some of the other graduate students in the lab group involves compounds other than TTT. • What is the primary source of Nellie's conflict? How might this conflict be avoided? • What constraints on a graduate student's research are appropriate? What constraints are not?

28. CASE 2 cont • Scenario 3 • Nellie decides to tell Katz the results of the experiments with DPP. He becomes irritated when she admits that she has conducted the experiments, and he informs her that if she wishes to continue her investigation of DPP, she will need to find another source of funding and another laboratory to work in. • Discussion Questions • Is it appropriate for Katz to accept funding that is restrictive (either explicitly or implicitly)? • Is it appropriate for Katz to allow Nellie to select a dissertation topic that could potentially conflict with funding constraints? How much latitude should a student be allowed in choice of a research topic? • Would Nellie's behavior be considered differently if she were working for a consulting firm with Katz as her supervisor rather than as a graduate student? How might public perception of her work change in this setting?

29. Publication Ethics Wiley publisher perspective https://authorservices.wiley.com/ethics-guidelines/index.html

30. Committee on Publication Ethics (COPE)

31. Some examples of publishing malpractice • Publication ethics • Unfair order of authors (not reflecting individual contributions to the work) • Undeclared conflict of interest (supporting body/ refereeing of grants or papers • Flawed peer review (grants and / or papers) • Publication strategies or games (split manuscripts to enhance the number of publications / duplication – data or narrative) • Poor acknowledgements • Ghost authors

32. CASE 3 Jack Fry was a chemical engineering post-doc in Dr Hill's lab, a multidisciplinary group of engineers, biologists and medical doctors. Jack had joined Hill's lab to improve his marketability for an academic position by gaining valuable research skills in the biological sciences. During his two year stay, Jack had collaborated with a surgeon in the group to test the utility of an experimental drug delivery system (DDS) in rats. DDS, developed by others in Hill's lab, delivered a toxic substance specifically to cancer cells, leaving non-cancerous cells intact. Jack and the surgeon were the first to test the effectiveness of DDS in living animals. They co-wrote a paper describing their initial findings; happily, a reputable journal has just accepted the paper for publication. https://www.onlineethics.org/Resources/gradres/gradresv1/jackfry.aspx

33. CASE 3 cont. Jack was now close to the end of his post-doctoral fellowship, and was once again actively seeking a faculty position in a chemical engineering department. Apparently his work in Hill's lab had improved his resume, because he immediately received an invitation to interview at a prestigious university. As part of the interview process, Jack was expected to give a 45-minute presentation in which he would discuss his research and conclude with his future research plans. Jack diligently prepared the presentation and gave a practice talk to his peers at the lab. The most common criticism was that Jack did not have enough engineering in his presentation, and that he should "find" some engineering to add to his talk to maximize his chances of getting hired. Jack approached Bob, a graduate student in the Hill lab, who had thoroughly studied and characterized the mechanism of DDS for the past two years and reported his need for more engineering material for his interview presentation. Bob began studying DDS about one year after its initial development, and had developed a detailed mathematical model of the system, including the mass transport of the drug to the cancer cells, the kinetics of cellular uptake of the drug, and the subsequent cell death. While developing the mathematical model, Bob had, on several occasions, received helpful advice and guidance from Jack, who had extensive experience in mathematical modeling. Bob was very grateful for Jack's help, and had thanked him publicly in the acknowledgment section of the paper that had recently been accepted for publication.

34. CASE 3 cont. Bob graciously agreed to help Jack. He spent an afternoon with Jack, discussing the mathematical model and bringing him up to speed on its details. Bob even loaned Jack some slides he had just made in preparation for an upcoming conference at which Bob would discuss his mathematical model. Jack thanked him for his help, and quickly updated his seminar presentation with Bob's mathematical model. At the interview, Jack presented his animal model data in conjunction with Bob's mathematical model. Jack did not mention Bob or the surgeon who had helped him conduct the animal studies in his talk, but his last slide, entitled "Acknowledgments", did list Bob and the surgeon as contributors to the work. The department, very impressed with the wide range of Jack's skills and the depth of his analysis of DDS, offered him a tenure track position.

35. CASE 3 cont. • Discussion Questions • Does Jack have an obligation to acknowledge Bob's contribution to the mathematical model? If so, did Jack satisfy this obligation? Would Jack's acknowledgment have changed if Bob had been in the audience? • Are decisions concerning attribution entirely Jack's responsibility? Should he consult others? How can one ensure that the work of professional colleagues is properly identified in an oral presentation? What, if any, were Hill's responsibilities in preparing Jack for his presentation? • Who else does Jack have obligations to? What are these obligations? Does Jack satisfy these obligations?

36. CASE 3 cont. • Discussion Questions • To what extent does a presentation at an interview resemble a publication? To what extent does it differ? • Did Jack misrepresent his own expertise and/or his own work on the project? What if his Ph.D. work had been all experimental and involved no mathematical modeling? • What, if any, are the obligations of the interviewers? Should they probe Jack's level of expertise? Is the type of lab Jack comes from likely to influence their evaluation of Jack's work?

38. Professionalism and integrity in research: dilemma game Developed by The Erasmus University Rotterdam • The dilemma game is available as interactive PDF here: http://www.eur.nl/fileadmin/ASSETS/ieb/integriteit/dilemmagame-mrg.pdf • Research Position: PhD student (e.g. dilemmas 54, 59, 62)