Review of NASA's Human Research Program Evidence Books: A Letter Report (2008)

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Committee on NASA’s Research on Human Health Risks June 18, 2008 Richard S. Williams, M.D. Chief Health and Medical Officer National Aeronautics and Space Administration Office of Health and Medical Systems 300 E Street, SW Washington, DC 20546 Dear Dr. Williams: At the request of the National Aeronautics and Space Administration (NASA), the Institute of Medicine (IOM)—under the auspices of the Standing Committee on Aerospace Medicine and the Medicine of Ex- treme Environments—established the Committee on NASA’s Research on Human Health Risks to examine NASA’s plans to assemble the avail- able evidence on human health risks of spaceflight and to move forward in identifying and addressing gaps in research. The body of this letter report provides the committee’s findings and recommendations regarding NASA’s compilation of the available evidence into reviews, or evidence books, as well as NASA’s risk identification and assessment process. Overall, the committee believes NASA has developed a thorough and well-conceived framework for documenting the evidence base, establish- ing research priorities, and integrating research findings into occupa- tional health and safety measures for the space crew. With the goal of further improving the process, the report offers its findings and recom- mendations (details below) relevant to: • Strengthening the content and format of the evidence books; and • Enhancing the process for updating and disseminating the evi- dence books. 1 

2 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS In addition, the committee offers specific suggestions to improve four of the evidence books as well as assessments of each evidence book (Ap- pendix C). CHARGE TO THE COMMITTEE In response to a request from the NASA Human Research Program, the IOM established an ad hoc committee to review each evidence book and assess the relevance of the identified human health-related risks for long-term spaceflight; appraise and clarify the descriptions of the risks; and assess the associated gaps in knowledge and identify additional areas for research (Box 1). Responding to NASA’s request, the IOM appointed the 12-member Committee on NASA’s Research on Human Health Risks with expertise in aerospace medicine, occupational health, preventive medicine, radia- tion medicine, bone loss, physiology/kinesiology, risk assessment and risk management, behavioral health, human performance, and cardiovas- cular and renal medicine. The committee met twice during the course of BOX-1 Statement of Task An ad hoc committee will assess the set of human health-related risks for long- term spaceflight and related research gaps identified by the National Aeronau- tics and Space Administration (NASA). The committee will build on the 2006 Institute of Medicine report, A Risk Re- duction Strategy for Human Exploration of Space: Review of NASA’s Bioastro- nautics Roadmap, in assessing the set of risks identified in NASA's Human Research Program Requirements Document (PRD). The committee will also draw on supplemental information compiled by NASA in a series of evidence books, which will be publicly available. Specifically, the committee will: • Assess the relevance of the identified health risks as potential threats to long-term space missions, including an assessment of the selec- tion of these risks from the larger set described in the Bioastronautics Roadmap; • Appraise and clarify the descriptions of the human health-related risks in the PRD; and • Assess the associated gaps in knowledge and identify additional ar- eas for research as necessary. 

LETTER REPORT 3 its work (Appendix A: Meeting Agenda). The first meeting was held in conjunction with a public data-gathering session with NASA staff, who provided program background and a review of the process used to gener- ate the evidence books. In addition, NASA staff provided the first four evidence books for initial discussion. At the second meeting, the commit- tee reviewed and assessed each evidence book, specifically evaluating each based on the following criteria: • Does the evidence book provide sufficient evidence that the risk is relevant to long-term space missions? • Is the text of the short description of the health risk provided in the Program Requirements Document (PRD) clear? • Does the evidence book make the case for the research gaps pre- sented? • Are there any additional gaps in knowledge that should be con- sidered for this specific risk? • Does the evidence book address relevant interactions among risks? • Is the expertise of the authors sufficient given the risk? • Are additional disciplines needed? • Is the breadth of the cited literature sufficient? • What is the overall readability and quality? The committee’s assessment of each of the 25 evidence books is provided in Appendix C. In discussing these assessments, the committee identified several overarching issues that it believed would be important for NASA to consider. Additionally, the committee examined NASA’s process for compiling and updating the evidence books. This letter report is based on the committee’s expert judgment and assessment of the evi- dence books provided by NASA. The committee did not conduct a for- mal assessment of research needs. This type of in-depth effort was not possible within the time allotted to the committee given the breadth of the topics and the scope of such a review. BACKGROUND Planning for long-duration space flights requires consideration of complex disease prevention, behavioral health, and clinical treatment issues—issues resulting from the hazards of the space environment and 

4 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS from limitations to in-mission medical care. These research and devel- opment needs have prompted NASA to seek and coordinate assessment from both national and international space medicine practice as well as biomedical research communities. In considering the multiple potential hazards and health issues re- lated to long-duration spaceflight, NASA staff developed the Bioastro- nautics Roadmap—a framework developed and used by NASA to assist in identifying research priorities and technology development, establish- ing exposure standards, and guiding resource allocation. In 2003, NASA requested that The National Academies conduct an evaluation of the Bioastronautics Roadmap. The resulting IOM report, A Risk Reduction Strategy for Human Exploration of Space: A Review of NASA’s Bio- astronautics Roadmap (IOM, 2006), focused its findings and recommen- dations on accelerating countermeasure and technology development; establishing a safe radiation exposure level for all relevant risks; and im- proving the process by which the content of the Roadmap was repre- sented, communicated, and kept current. Among the recommendations relevant to this study were incorporating quality-of-evidence measures for risks; representing risk severity separately from the state of the miti- gation strategy or countermeasure; using standard uncertainty analysis techniques to quantify risk uncertainty; and ensuring that the Roadmap is viewed as a dynamic and current database rather than simply a static document. In addition, in 2007 the IOM released a letter report, Review of NASA’s Space Flight Health Standards-Setting Process: Letter Re- port, that provided NASA with a set of recommendations on how it es- tablishes space flight health standards for human performance (IOM, 2007). Building on the Bioastronautics Roadmap, NASA’s Human Re- search Program (HRP) has developed a new process within the past year to ensure proper attention is given to addressing potential human health risks. This process includes the compilation of the Program Require- ments Document, which focuses on 28 specific health risks (see Appen- dix B for a table showing the relationship of these risks with the risks in the Bioastronautics Roadmap and PRD) (NASA, 2008a). The evidence base was compiled into a series of 25 evidence books, each of which re- views the spaceflight and ground evidence relevant to the specific risk (NASA, 2008b). The initial set of evidence books was compiled by NASA using specific guidelines developed by NASA and provided to the committee for their review. The purpose of the evidence books is to document and review the available evidence supporting the identification 

LETTER REPORT 5 of each performance risk identified in the HRP Program Requirements Document but not to provide strategic guidance for how NASA may wish to mitigate the associated risks. The goal is to periodically update these reviews and establish a record of the current state of knowledge associated with each risk (NASA, Human Research Program Integrated Research Plan, HRP 47065). The content of these evidence books and the process by which risks were selected for inclusion provides the basis for this letter report. At the committee’s first meeting, NASA staff provided a briefing on the Human Research Program’s continuous risk management process— an iterative process focused on assessing how best to prevent and treat injuries, illnesses, or concerns regarding the health of the spaceflight crew. The process being set in place by the HRP calls for the following: • Identification of the health risks through the Bioastronautics Roadmap and through the risk forums (Box 2); • Assessment of the evidence base through the development and refinement of the series of evidence books: • Review of the evidence and gaps in the research base through the risk forums and reviews by standing review panels (Box 2); • Developing, awarding, and implementing research grants and contracts; and • Review of research results by NASA. Research data from multiple sources are then incorporated into pre- vention and mitigation strategies used in spaceflight; these can serve as the basis of future research and of improvements for future spaceflights. This report addresses the early stages of this process. FINDINGS REGARDING SPECIFIC EVIDENCE BOOKS The committee commends NASA for taking the initial steps of as- sembling the documentation of scientific knowledge regarding the risks that have highest relevance to human health during long-duration space- flight beyond low Earth orbit. These evidence books are part of a broader process to prioritize risks and associated research needs and to identify mitigation strategies. While the committee found specific areas for im- provement in each of the evidence books—including in some cases 

6 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS BOX-2 Human Research Program Risk Forums and the Human System Risk Board NASA’s Human Research Program (HRP) is in the process of establishing and implementing risk forums, which will meet regularly (as often as twice a month) to promote cross-disciplinary discussion about each health risk as well as considering potential new topics that should be explored. The mem- bership of the forum includes the chief medical officer, who serves as the forum’s chair; the senior flight surgeon; a senior representative for Physiol- ogy; a senior representative for Environmental Factors; a senior representa- tive for Human Factors; a representative from the Astronaut Office; an International Space Station/Shuttle Transportation System representative; a Constellation Program representative; and the Program Manager from HRP. These individuals also make up the membership of the Human System Risk Board, which is responsible for ensuring that a consistent, integrated process is established and maintained for managing human system risks; advising the Health and Medical Technical Authority and other relevant program represen- tatives concerning the status, coordination, integration, mitigation, and re- search strategy of all human system risks; and facilitating human system risk management in support of the chief medical officer (Personal communication, C. Kundrot, NASA, April 1, 2008). Anyone is permitted to bring forward a potential health risk to the Human Sys- tem Risk Board. To do so the board requires that the potential risk be de- scribed in the form of a “risk statement,” describing the risk context and any available evidence. For example, the statements include any available evi- dence of pre- or postflight incidence, similar risks in analog terrestrial popula- tions, relevant case studies, and expert opinion from relevant communities. The Board also reviews the potential risks for relevance to the mission, in- cluding, among other things, operational mission impact, acute and long-term health risks, and performance impacts. the need to improve the relevancy of the identified risks and discussion of additional knowledge gaps and potential associations between related risks—overall the committee believes that they are valuable resources and important components to the overall process, reflecting the current state of knowledge on health risks associated with spaceflight, and be- lieves if the evidence books are kept current, their value will increase over time. Through continued improvements and updates the evidence books will help communicate gaps in knowledge and the resulting needs for research and development and will provide an archive of progress made in understanding health risks of human space flight. The committee offers its findings and recommendations with the goal of improving future versions of the evidence books. The committee 

LETTER REPORT 7 hopes that maintaining these up-to-date summaries of the state of knowl- edge on human health risks of spaceflight will continue to be a priority at NASA and that the committee’s comments will be useful in improving the process by which that is done. In addition to the committee’s overall findings and recommenda- tions, this report offers specific comments for each evidence book that are included in Appendix C. Further, the committee makes a number of suggestions to address instances in the set of evidence books where there was unevenness, lack of clarity in the scope of the review, readability issues, or other issues such as lack of definition of physiological re- quirements and benchmarks. Modifying the Scope and Focus of the Evidence Books The committee found the identified health risks to be largely relevant as potential threats to long-term space missions. As discussed below and in the individual reviews in Appendix C, some of the evidence books would benefit from increased clarity or change in scope. In a few cases, the committee found that although the risks that were identified in the PRD were of clear significance, the focus of the evidence books could be broadened to better address the breadth of potential risks and research gaps. In particular, the committee has the following comments regarding four specific evidence books: • #7: Operational Impact of Prolonged Daily Exercise; • #10: Cardiovascular Effects on Performance and Operational Limitations; • #16: Behavioral and Psychiatric Conditions; and • #23: Lack of Human-Centered Design. Operational Impact of Prolonged Daily Exercise Evidence book #7, Operational Impact of Prolonged Daily Exercise, discusses an issue that is considerably broader in scope than the current title implies. Exercise is only one possible countermeasure against physiological deconditioning, and is neither fully effective nor opera- tionally satisfactory at this time. The current iteration of the evidence book provides a brief overview of the issue and acknowledges that no 

8 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS evidence exists to support this potential risk; furthermore, no references are provided. As written, there is no evidence to support the inclusion of this risk in the PRD. However, the committee agrees that it is self- evident that a competition for time exists between countermeasure pro- grams and other mission demands. In a broader context, many opera- tional tensions are present for any human risk mitigation (countermeasure) strategy, including competition for consumable re- sources (e.g., food, water, oxygen) as well as the mass, volume, and power that a countermeasure may require (e.g., exercise equipment, ra- diation shielding). Thus, the problem is one of systems engineering in which the human is a recognized subsystem. The committee believes this is a valid area for research and development that has characteristics unique to spaceflight. Because the central challenge is one of systems engineering, this risk spans the Human Research Program and the Exploration Technology Development Program. To some extent, research from analog environ- ments may help populate the evidence base. For example, data collected from nuclear submarines may be relevant in some circumstances since submarines have volume, time, and consumable resource restraints not altogether different from spaceflight. The committee suggests changing the scope of the evidence book to Operational Impact of Countermea- sures. The scope of this risk should be broadened to include the effects of countermeasure testing, effectiveness, crew acceptability, and implemen- tation on both spacecraft and mission design. Cardiovascular Effects on Performance and Operational Limitations The committee found that the topic of evidence book #10, Cardio- vascular Effects on Performance and Operational Limitations, is a subset of the broader issue of the effects of decrements in work capacity on op- erational performance. In some cases that involve sustained higher level energy expenditure (e.g., “the lunar 10K walk back” scenario), the car- diovascular system may indeed be limiting. In other cases such as extra vehicular activity, muscle strength and endurance may be limiting fac- tors. The committee believes the common consideration is that physio- logical systems may limit physical work capacity, but the specific system that creates a concern will depend on the unique requirements of an op- erational task. 

LETTER REPORT 9 The committee suggests that this risk should be redefined to Physio- logical Limits on Performance and Operations to include effects such as cardiovascular, metabolic, strength, and thermal limits that might cause operational tasks to be limited or redefined. Setting physiological re- quirements for mission-related tasks and adequate assessment methods for each will help guide the effectiveness of the countermeasure program in maintaining each system for operational performance. Behavioral and Psychiatric Conditions In reviewing evidence book #16, Behavioral and Psychiatric Condi- tions, the committee found that it did not include any substantive review of those features of personality and behavioral performance that would be most likely to promote effective crew performance (and thus might become “select-in” criteria). Such a review would be a valuable addition to the white paper that would likely identify important knowledge gaps in the behavioral assessment plan. Current research and understanding of the manifestation of behavioral and psychiatric problems in space are, simply stated, inadequate, and from the perspective of a balanced ap- proach, little attention has been paid to potential psychological benefits of spaceflight. The committee appreciates that the absence of a body of detailed quantitative evidence concerning behavioral and psychiatric problems in space is understandable, given the sensitivity of the topic and privacy concerns. Behavioral and psychiatric problems have been viewed as operational medical issues that are held confidential, rather than as a health-related research agenda that deserves co-equal status with somatic health issues. The committee believes the potential serious- ness of the psychological and behavioral health risks highlights the need for the evidence book to contain a review and any relevant data, includ- ing an analysis of newer instruments and scales for evaluating more sub- tle personality differences. Including this information will also point to potential associated research gaps. In addition, the committee notes that the extensive list of current countermeasures is tied neither to the pub- lished evidence base of psychological interventions nor to measures of effectiveness. A systematic evaluation of current and proposed counter- measures should be included in future iterations of the evidence book. 

10 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Lack of Human-Centered Design Evidence book #23, entitled Lack of Human-Centered Design, ad- dresses three risks related to human factors—inadequate information, poor human factor design, and poor task design. The committee had three concerns with this evidence book. First, the committee believes the information-related issues are sufficiently distinct from the other human factors issues, and sufficiently related to other issues beyond the human factors issues, to warrant a discussion and review of the evidence in a stand-alone evidence book. Moreover, this review should consider not only inadequate information, but also excessive information and the po- tential cognitive overload resulting from an overabundance of informa- tion of varying degrees of priority, improperly presented, that can increase the risk of error or jeopardize safety. Second, the topics of task design and human factor design need to be more clearly defined and more sharply distinguished from each other. The risks are important, but they need to be presented in a manner that more closely reflects the es- tablished discipline of human factors engineering, and less in general terms of systems effectiveness. The committee suggests that the differ- ences and interrelationships between these two areas be clarified so that the redundancies and overlaps in the current evidence book can be elimi- nated. The committee recommends that the evidence books focus on ex- amples that are of greater specificity and relevance to spaceflight human factors issues, rather than more generalized examples of crises. The committee believes that by eliminating or greatly shortening many of the ground-based examples, such as Three Mile Island or the Titanic, in the current evidence book the value of specific human factor examples in space will be significantly enhanced. OVERARCHING FINDINGS AND RECOMMENDATIONS The committee organized its recommendations into two broad areas: (1) issues focused on strengthening the content and format of the evi- dence books, and (2) issues relevant to improving the process of updating and disseminating the evidence on human health risks. 

LETTER REPORT 11 Strengthen the Content and Format of the Evidence Books Recommendation 1: Strengthen the Content and Format of the Evidence Books NASA should continue to refine its evidence books and work to ensure further consistency and depth of analysis. Specifically, NASA should: • Require that all evidence reviews use the quality-of-evidence criteria; • Encourage a broader review of all relevant literature and knowledge bases, including in- flight data and other relevant data sources (e.g., NASA Life Sciences Data Archive, Lon- gitudinal Study of Astronauts’ Health, data from other space agencies); • Include, or link to, a summary of the current state of knowledge regarding countermea- sures and the plan to mitigate risk; • Improve the consistency and organization of the discussions on identified research gaps; • Increase the emphasis on potential postflight and long-term health outcomes; and • Develop evidence books on additional risks, including alterations in microbe and host in- teractions and impaired healing function. Expand the Literature Base and Categorize the Quality of Evidence The authors of the evidence books were asked to include the risk statements as they were written in the PRD, and review the risks based on published and unpublished scientific and clinical evidence from data collected from space- and ground-based research on humans, animals, and other models. This resulted in a wide variety and quality of cited data, such as unpublished results, observational studies, meta-analyses, and randomized trials. In this context, the evidence books varied considerably in the scope of the published and unpublished data reviewed. In addition to a compre- hensive review of all relevant terrestrial and space published data, the 

12 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS committee encourages the authors to explore data from other sources. For example, reviews of data from international space agencies are par- ticularly relevant and should be added where possible. Furthermore, au- thors should be encouraged to review the NASA Life Sciences Data Archive for relevant data (http://lsda.jsc.nasa.gov/). However, the com- mittee recognizes the potential limitations associated with these data sources and encourages NASA’s HRP to collaborate with its program- matic partners to expand pre-, in-, and post-flight data collection. In NASA’s instructions the authors of the evidence books were en- couraged, but not required, to label evidence using its four categories.1 However, to clarify the type of evidence presented and to provide addi- tional information regarding the strength of evidence, the committee be- lieves NASA should require authors to use categories of evidence in future versions of the evidence books, while recognizing that experience with the explicit categorization of evidence may be refined over time, particularly regarding the categories used. Apart from the absence of quality-of-evidence criteria, the first evidence book, Impaired Ability to Maintain Control of Vehicles and Other Complex Systems, stands out as a model for the clear presentation of a risk, the relevant evidence, and associated research gaps. As a general observation, the committee found that the evidence books focused more on short-term health outcomes associated with spe- cific risks, and in several circumstances did not include a discussion of the relevant potential long-term health outcomes associated with that risk. The committee encourages NASA to expand its reviews to ac- knowledge potential long-term health outcomes. Consideration should be given to including this as a standard element of an evidence book outline, wherever appropriate. 1 Type I: at least one randomized, controlled trial. Type II: at least one controlled study without randomization, including cohort, case-control, or subject operating as own con- trol. Type III: nonexperimental observations or comparative, correlation, and case or case-series studies opinion. Type IV: expert committee reports or opinions of respected authorities based on clinical experiences, bench research, or “first principles” (NASA, 2008b). 

LETTER REPORT 13 Improve Consistency of Writing Teams The composition of the writing group and their understanding of the task varied considerably across the evidence books. Because the evi- dence supporting a particular risk must capture and summarize the knowledge base adequately, the teams constructing the evidence books must be knowledge-domain experts, working in a manner that is collabo- rative (teamwork), scholarly (academic), and egalitarian (nonadvocates for funding in their research area, working for the overall health and safety of astronauts). Some evidence books were authored by a dozen or more individuals with a mix of knowledge experts and program managers, while others were authored by a single individual. The committee recognizes that team quality contributes directly to the scientific rigor and excellence of the evidence book; however, NASA did not appear to use a standard set of selection criteria for choosing the authors for each evidence book. In addition, once chosen it was not clear how each team member interacted and contributed to the final evidence book. Consequently, NASA should develop a consistent process for selecting authors and should implement standards for authorship based on assigning responsibility and giving credit for intellectual work, similar to those used by peer-reviewed jour- nals. Statements regarding disclosure of conflicts of interest should also be required. Summarize the State of the Knowledge on Countermeasures Each evidence book included the primary knowledge gaps associated with each risk, as identified by the authors. Although the authors were instructed not to address potential mitigation strategies or known mitiga- tion gaps, the committee believes that countermeasures are an important component of the evidence books and are integral to understanding the current state of scientific knowledge and the severity of the potential im- pact of the risks on the individual and the mission. To this end the au- thors should provide a link to a review of the state of knowledge on countermeasures. This review should include a discussion of the impact that countermeasures have had on risk mitigation and the identified re- search gaps, including countermeasures that have been implemented in space and those that been tested on the ground. Please note that, consis- tent with the Bioastronautics Roadmap review, care should be taken 

14 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS to separate the description of the risk from the description of counter- measures. Improve Consistency and Organization of Research Gaps There is a great deal of variability in how the evidence books present and organize the associated gaps in knowledge and research. Since one of the major goals of the evidence books is to provide the evidence base on which to improve human health and reduce health risks associated with spaceflight, it is important to organize the discussion of research gaps so that their operational impact will be evident and the type of re- search or other actions needed to move forward is clearly defined. There- fore, the committee encourages NASA to develop a more uniform approach to how the gaps associated with each risk are presented. Each evidence book would be strengthened, for example, if it identified and organized the section on research gaps according to the following 5 spe- cific categories or a similar categorical system: 1. Preventing and screening for avoidable in-flight events; 2. Managing the physiological adaptation to spaceflight during missions and to prevent long-term health consequences after- ward; 3. Management of environmental factors, their effects, and poten- tial countermeasures to these effects (e.g., radiation, lunar dust, atmospheric pressure, hypoxia); 4. Providing optimal treatment for biomedical events in space, rec- ognizing limitations associated with space travel; and 5. Improving human factors design and the human-machine inter- face. In circumstances when the above categorization is not directly appli- cable to the research gap, NASA should encourage the authors to provide details on recommended next steps. Add Additional Health Risks In its assessment of the set of evidence books, the committee noted two potential risks that were not addressed, but that the committee be- 

LETTER REPORT 15 lieved should be given consideration for inclusion in at least the “watch list” of possible risks. These include the risk of alterations in microbe and host interactions and the risk of impaired healing function. The risk of alterations in microbial pathogenicity was highlighted by a recent pub- lication describing the bacterial pathogen Salmonella typhimurium grown aboard space shuttle mission STS-115 and compared with identi- cal ground control cultures. Spaceflight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumula- tion consistent with a biofilm (Wilson et al., 2007). The risk of impaired bone and wound healing function was derived from experiments con- ducted with rats on STS-57 and Cosmos 2044 missions (Davidson et al., 1999) and rat hind-limb unloading models (Radek et al., 2008). In addi- tion, there is anecdotal evidence from Mir to suggest that healing of mi- nor cuts or abrasions may be delayed. The implications of poor wound healing, combined with the statistical prediction of the likelihood of traumatic injury contained in the evidence book on the risk of inadequate medical care, make a compelling case for an expanded research program in this area. Continue to Improve NASA’s Process for Updating and Disseminat- ing the Evidence on Human Health Risks The committee believes NASA has developed a thorough and well- conceived framework for documenting the evidence base, establishing research priorities, and integrating research findings into occupational health and safety measures for the space crew. The process may benefit from (1) enhanced mechanisms to review and update the evidence books, especially through the involvement of the extramural research commu- nity; (2) developing a public dissemination strategy; and (3) using all available data sources. Recommendation 2: Enhance the Process for Updat- ing and Disseminating the Evidence Books NASA should continue to refine and strengthen its processes for updating the evidence books, identify- ing potential new risks, and revisiting retired risks. Specifically, NASA should: 

16 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS • Create a transparent, verifiable process for PRD risk definition and inclusion; • Summarize the evidence for potential risks that are listed on the watch list; • Engage a broad community of experts in re- viewing and updating the content of the evi- dence books, including experts from outside the intramural NASA program; • Update the evidence books via periodically scheduled and event-driven reviews (e.g., af- ter major new studies are published); • Create a process to retain and update the evi- dence base for risks that have been mitigated to an acceptable level; and • Disseminate the evidence books to all relevant stakeholders and the general public. Reviewing and Updating the Evidence Books The committee encourages NASA to broaden the responsibility of the risk forums and Human System Risk Board by integrating into these mechanisms a formal and documented strategy for periodically review- ing and updating the evidence books. NASA plans annual reviews of the current set of evidence books; however, the process for these reviews is still in development. The com- mittee believes the following issues need clarification: • How were the risks in the evidence books defined? For example, what were the criteria used to change wording, collapse a Bio- astronautics Roadmap risk into a single PRD risk, or decompose a Roadmap risk into many PRD risks (see Appendix B)? • Are alterations in a risk definition validated with the Roadmap authors to ensure correct translation of the risk? • What are the decision criteria used to choose which risks are se- lected for the active list and developed into evidence books and which are left on the “watch list”? • What is the decision-making process to move or remove a risk to or from the “watch list”? 

LETTER REPORT 17 NASA is encouraged to establish a formal and documented plan for defining and updating risk statements. Furthermore, NASA should re- view not only the risks described in the evidence books, but also those that have been placed on the “watch list” and potential new risks that may not have been examined previously, to determine whether they may be affected by any new scientific or clinical results. Specifically, the committee believes it would be useful to develop evidence books on risks that are on the “watch list” to make explicit the current level of evi- dence. The concept of “retiring risks” when adequately effective coun- termeasures become available seems fraught with the concern that those risks, although adequately mitigated, will cease to be considered as haz- ards for operational planning. Therefore the committee recommends that they be maintained in a category named “risks with adequate counter- measures” rather than “retired” unless some fundamental change in the environment or mission profile renders them irrelevant and their associ- ated countermeasures unnecessary. In some circumstances a formal, quantitative uncertainty analysis approach would provide structure, discipline, and transparency for the decision process. The process provides a basis for interim decision mak- ing in the absence of needed data and for identifying questions for which more information is most needed because of possible or likely conse- quences for mission success and long-term health effects (IOM, 2006). Used elsewhere in NASA, this approach could assist in the evaluation of the evidence books and as part of the overall process of NASA’s priority- setting and risk management decision-making. It may also be valuable for NASA to attach to each risk two numbers (or interval estimates of two numbers): (1) rough (order-of-magnitude) estimates of severities of health effects (e.g., measured in quality- adjusted life years); and (2) rough estimates of their probabilities, for different scenarios (e.g., with and without deployment of specific coun- termeasures). The goal would be to provide NASA health risk managers and other stakeholders with an indication of the approximate sizes of the risks for different health effects (based on their probability and severity estimates), and of the sizes of risk reductions achieved by different coun- termeasures. This may help NASA to set priorities and allocate its lim- ited resources to benefit astronaut health as much as possible. Basic comparative information regarding probabilities and severities of risks relative to one another may contribute to understanding, interpreting, and communicating the practical risk management implications of the re- search summarized in the evidence books. 

18 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Expanding the Evidence Base and External Input The authors of each evidence book included representatives from the NASA research and medical operations community and the National Space Biomedical Research Institute. However, to help ensure that rele- vant scientific and clinical evidence not traditionally considered by NASA scientists is included in the evidence book, NASA is encouraged to include expertise from outside the immediate intramural and extramu- ral NASA community in drafting and reviewing the evidence books. Fur- thermore, NASA should establish a formal peer-review, publication, and public dissemination strategy to help ensure that all evidence and state- ments included in the evidence books meet the appropriate high stan- dards used for each particular area of interest. External input would also be valuable as part of the risk forum process (Box 2) that NASA is using to identify new risks and to move forward in refining NASA’s risk man- agement strategy. NASA is encouraged to proactively and periodically survey a broader external community—including individuals not associ- ated with its human health risk program—to assist in the above efforts and to identify any new potential risks that may have been overlooked before. NASA may wish to take advantage of newer methods of commu- nity-based editing, such as the Wikipedia model, by inviting appropri- ately credentialed and authorized experts in the areas covered by the risk evidence books to interactively update the current best evidence online. Because opportunities for data collection on human response to mi- crogravity and other relatively unique aspects of space exploration are so limited, NASA needs to fully employ the available methods and venues to collect and analyze astronaut health data. This report acknowledges the issues discussed in previous IOM reports (IOM, 2001, 2004, 2006, 2007) regarding taking full advantage of opportunities for data collection on the health of the space crew. Further, studies of the experiences in polar environments and of Navy submarine crews are excellent sources of data on analog environments. In addition, to expanding the inclusion of relevant spaceflight and outcomes data, authors should be encouraged to use all available data sources, such as the NASA Life Sciences Data Archive (including the Longitudinal Study of Astronauts’ Health), and data from other space agencies. Attention to intercultural issues and chal- lenges in communication and relationships are among the many issues to be explored through data from multinational efforts.