Integrating value of research into NCI Clinical Trials Cooperative Group research review and prioritization: A pilot study

BackgroundThe Institute of Medicine has called for approaches to help maximize the return on investments (ROI) in cancer clinical trials. Value of Research (VOR) is a health economics technique that estimates ROI and can inform research prioritization. Our objective was to evaluate the impact of using VOR analyses on the clinical trial proposal review process within the SWOG cancer clinical trials consortium.MethodsWe used a previously developed minimal modeling approach to calculate VOR estimates for 9 phase II/III SWOG proposals between February 2015 and December 2016. Estimates were presented to executive committee (EC) members (N = 12) who determine which studies are sent to the National Cancer Institute for funding consideration. EC members scored proposals from 1 (best) to 5 based on scientific merit and potential impact before and after receiving VOR estimates. EC members were surveyed to assess research priorities, proposal evaluation process satisfaction, and the VOR process.ResultsValue of Research estimates ranged from −$2.1B to$16.46B per proposal. Following review of VOR results, the EC changed their score for eight of nine proposals. Proposal rankings were different in pre‐ vs postscores (P value: 0.03). Respondents had mixed views of the ultimate utility of VOR for their decisions with most supporting (42%) or neutral (41%) to the idea of adding VOR to the evaluation process.ConclusionsThe findings from this pilot study indicate use of VOR analyses may be a useful adjunct to inform proposal reviews within NCI Cooperative Clinical Trials groups.The Instiztute of Medicine has called for approaches to help maximize the return on investments in cancer clinical trials. The findings from this pilot study indicate use of value of research analyses may be a useful adjunct to inform proposal reviews within NCI Cooperative Clinical Trials groups.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146484/1/cam41657.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146484/2/cam41657_am.pd

Cuts and flows of cell complexes

We study the vector spaces and integer lattices of cuts and flows associated with an arbitrary finite CW complex, and their relationships to group invariants including the critical group of a complex. Our results extend to higher dimension the theory of cuts and flows in graphs, most notably the work of Bacher, de la Harpe and Nagnibeda. We construct explicit bases for the cut and flow spaces, interpret their coefficients topologically, and give sufficient conditions for them to be integral bases of the cut and flow lattices. Second, we determine the precise relationships between the discriminant groups of the cut and flow lattices and the higher critical and cocritical groups with error terms corresponding to torsion (co)homology. As an application, we generalize a result of Kotani and Sunada to give bounds for the complexity, girth, and connectivity of a complex in terms of Hermite's constant.Comment: 30 pages. Final version, to appear in Journal of Algebraic Combinatoric

Co-ordinated expression of amino acid metabolism in response to N and S deficiency during wheat grain filling

Increasing demands for productivity together with environmental concerns about fertilizer use dictate that the future sustainability of agricultural systems will depend on improving fertilizer use efficiency. Characterization of the biological processes responsible for efficient fertilizer use will provide tools for crop improvement under reduced inputs. Transcriptomic and metabolomic approaches were used to study the impact of nitrogen (N) and sulphur (S) deficiency on N and S remobilization from senescing canopy tissues during grain filling in winter wheat (Triticum aestivum). Canopy tissue N was remobilized effectively to the grain after anthesis. S was less readily remobilized. Nuclear magnetic resonance (NMR) metabolite profiling revealed significant effects of suboptimal N or S supply in leaves but not in developing grain. Analysis of amino acid pools in the grain and leaves revealed a strategy whereby amino acid biosynthesis switches to the production of glutamine during grain filling. Glutamine accumulated in the first 7 d of grain development, prior to conversion to other amino acids and protein in the subsequent 21 d. Transcriptome analysis indicated that a down-regulation of the terminal steps in many amino acid biosynthetic pathways occurs to control pools of amino acids during leaf senescence. Grain N and S contents increased in parallel after anthesis and were not significantly affected by S deficiency, despite a suboptimal N:S ratio at final harvest. N deficiency resulted in much slower accumulation of grain N and S and lower final concentrations, indicating that vegetative tissue N has a greater control of the timing and extent of nutrient remobilization than S

The Global Task Force for Chronic Pain in People with HIV (PWH):Developing a research agenda in an emerging field

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward

Principles and Practices of Neurodevelopmental Assessment in Children: Lessons Learned from the Centers for Children’s Environmental Health and Disease Prevention Research

Principles and practices of pediatric neurotoxicology are reviewed here with the purpose of guiding the design and execution of the planned National Children’s Study. The developing human central nervous system is the target organ most vulnerable to environmental chemicals. An investigation of the effects of environmental exposures on child development is a complex endeavor that requires consideration of numerous critical factors pertinent to a study’s concept, design, and execution. These include the timing of neurodevelopmental assessment, matters of biologic plausibility, site, child and population factors, data quality assurance and control, the selection of appropriate domains and measures of neurobehavior, and data safety and monitoring. Here we summarize instruments for the assessment of the neonate, infant, and child that are being employed in the Centers for Children’s Environmental Health and Disease Prevention Research, sponsored by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, discuss neural and neurobiologic measures of development, and consider the promises of gene–environment studies. The vulnerability of the human central nervous system to environmental chemicals has been well established, but the contribution these exposures may make to problems such as attention deficit disorder, conduct problems, pervasive developmental disorder, or autism spectrum disorder remain uncertain. Large-scale studies such as the National Children’s Study may provide some important clues. The human neurodevelopmental phenotype will be most clearly represented in models that include environmental chemical exposures, the social milieu, and complex human genetic characteristics that we are just beginning to understand

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

A thematic analysis of factors influencing recruitment to maternal and perinatal trials

Background: Recruitment of eligible participants remains one of the biggest challenges to successful completion of randomised controlled trials (RCTs). Only one third of trials recruit on time, often requiring a lengthy extension to the recruitment period. We identified factors influencing recruitment success and potentially effective recruitment strategies. Methods: We searched MEDLINE and EMBASE from 1966 to December Week 2, 2006, the Cochrane Library Methodology Register in December 2006, and hand searched reference lists for studies of any design which focused on recruitment to maternal/perinatal trials, or if no studies of maternal or perinatal research could be identified, other areas of healthcare. Studies of nurses' and midwives' attitudes to research were included as none specifically about trials were located. We synthesised the data narratively, using a basic thematic analysis, with themes derived from the literature and after discussion between the authors. Results: Around half of the included papers (29/53) were specific to maternal and perinatal healthcare. Only one study was identified which focused on factors for maternal and perinatal clinicians and only seven studies considered recruitment strategies specific to perinatal research. Themes included: participant assessment of risk; recruitment process; participant understanding of research; patient characteristics; clinician attitudes to research and trials; protocol issues; and institutional or organisational issues. While no reliable evidence base for strategies to enhance recruitment was identified in any of the review studies, four maternal/perinatal primary studies suggest that specialised recruitment staff, mass mailings, physician referrals and strategies targeting minority women may increase recruitment. However these findings may only be applicable to the particular trials and settings studied. Conclusion: Although factors reported by both participants and clinicians which influence recruitment were quite consistent across the included studies, studies comparing different recruitment strategies were largely missing. Trials of different recruitment strategies could be embedded in large multicentre RCTs, with strategies tailored to the factors specific to the trial and institution.Rebecca L Tooher, Philippa F Middleton and Caroline A Crowthe

Acceptability of the 6-PACK falls prevention program: A pre-implementation study in hospitals participating in a cluster randomized controlled trial

There is limited evidence to support the effectiveness of falls prevention interventions in the acute hospital setting. The 6-PACK falls prevention program includes a fall-risk tool; 'falls alert' signs; supervision of patients in the bathroom; ensuring patients' walking AIDS are within reach; toileting regimes; low-low beds; and bed/chair alarms. This study explored the acceptability of the 6-PACK program from the perspective of nurses and senior staff prior to its implementation in a randomised controlled trial. A mixed-methods approach was applied involving 24 acute wards from six Australian hospitals. Participants were nurses working on participating wards and senior hospital staff including: Nurse Unit Managers; senior physicians; Directors of Nursing; and senior personnel involved in quality and safety or falls prevention. Information on program acceptability (suitability, practicality and benefits) was obtained by surveys, focus groups and interviews. Survey data were analysed descriptively, and focus group and interview data thematically. The survey response rate was 60%. Twelve focus groups (n = 96 nurses) and 24 interviews with senior staff were conducted. Falls were identified as a priority patient safety issue and nurses as key players in falls prevention. The 6-PACK program was perceived to offer practical benefits compared to current practice. Nurses agreed fall-risk tools, low-low beds and alert signs were useful for preventing falls (>70%). Views were mixed regarding positioning patients' walking aid within reach. Practical issues raised included access to equipment; and risk of staff injury with low-low bed use. Bathroom supervision was seen to be beneficial, however not always practical. Views on the program appropriateness and benefits were consistent across nurses and senior staff. Staff perceived the 6-PACK program as suitable, practical and beneficial, and were open to adopting the program. Some practical concerns were raised highlighting issues to be addressed by the implementation plan