Exploratory studies to inform full-scale evaluations of complex public health interventions: the need for guidance

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Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes

Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions

Development of the Knee Quality of Life (KQoL-26) 26-item questionnaire: data quality, reliability, validity and responsiveness

Background This article describes the development and validation of a self-reported questionnaire, the KQoL-26, that is based on the views of patients with a suspected ligamentous or meniscal injury of the knee that assesses the impact of their knee problem on the quality of their lives. Methods Patient interviews and focus groups were used to derive questionnaire content. The instrument was assessed for data quality, reliability, validity, and responsiveness using data from a randomised trial and patient survey about general practitioners' use of Magnetic Resonance Imaging for patients with a suspected ligamentous or meniscal injury. Results Interview and focus group data produced a 40-item questionnaire designed for self-completion. 559 trial patients and 323 survey patients responded to the questionnaire. Following principal components analysis and Rasch analysis, 26 items were found to contribute to three scales of knee-related quality of life: physical functioning, activity limitations, and emotional functioning. Item-total correlations ranged from 0.60–0.82. Cronbach's alpha and test retest reliability estimates were 0.91–0.94 and 0.80–0.93 respectively. Hypothesised correlations with the Lysholm Knee Scale, EQ-5D, SF-36 and knee symptom questions were evidence for construct validity. The instrument produced highly significant change scores for 65 trial patients indicating that their knee was a little or somewhat better at six months. The new instrument had higher effect sizes (range 0.86–1.13) and responsiveness statistics (range 1.50–2.13) than the EQ-5D and SF-36. Conclusion The KQoL-26 has good evidence for internal reliability, test-retest reliability, validity and responsiveness, and is recommended for use in randomised trials and other evaluative studies of patients with a suspected ligamentous or meniscal injury

Getting our ducks in a row:The need for data utility comparisons of healthcare systems data for clinical trials

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS.METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status.DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.</p

Getting our ducks in a row:The need for data utility comparisons of healthcare systems data for clinical trials

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS.METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status.DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.</p

Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials

Background: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. “Data Utility Comparison Studies” (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. // Methods-and-Results: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at “patient-level” or “trial-level”, depending on the item of interest and trial status. // Discussion: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them

Applying an extended theoretical framework for data collection mode to health services research

<p>Abstract</p> <p>Background</p> <p>Over the last 30 years options for collecting self-reported data in health surveys and questionnaires have increased with technological advances. However, mode of data collection such as face-to-face interview or telephone interview can affect how individuals respond to questionnaires. This paper adapts a framework for understanding mode effects on response quality and applies it to a health research context.</p> <p>Discussion</p> <p>Data collection modes are distinguished by key features (whether the survey is self- or interviewer-administered, whether or not it is conducted by telephone, whether or not it is computerised, whether it is presented visually or aurally). Psychological appraisal of the survey request will initially entail factors such as the cognitive burden upon the respondent as well as more general considerations about participation. Subsequent psychological response processes will further determine how features of the data collection mode impact upon the quality of response provided. Additional antecedent factors which may further interact with the response generation process are also discussed. These include features of the construct being measured such as sensitivity, and of the respondent themselves (e.g. their socio-demographic characteristics). How features of this framework relate to health research is illustrated by example.</p> <p>Summary</p> <p>Mode features can affect response quality. Much existing evidence has a broad social sciences research base but is of importance to health research. Approaches to managing mode feature effects are discussed. Greater consideration must be given to how features of different data collection approaches affect response from participants in studies. Study reports should better clarify such features rather than rely upon global descriptions of data collection mode.</p

A randomised controlled trial to compare opt-in and opt-out parental consent for childhood vaccine safety surveillance using data linkage: study protocol

Extent: 10p.Background: The Vaccine Assessment using Linked Data (VALiD) trial compared opt-in and opt-out parental consent for a population-based childhood vaccine safety surveillance program using data linkage. A subsequent telephone interview of all households enrolled in the trial elicited parental intent regarding the return or non-return of reply forms for opt-in and opt-out consent. This paper describes the rationale for the trial and provides an overview of the design and methods. Methods/Design: Single-centre, single-blind, randomised controlled trial (RCT) stratified by firstborn status. Mothers who gave birth at one tertiary South Australian hospital were randomised at six weeks post-partum to receive an opt-in or opt-out reply form, along with information explaining data linkage. The primary outcome at 10 weeks post-partum was parental participation in each arm, as indicated by the respective return or non-return of a reply form (or via telephone or email response). A subsequent telephone interview at 10 weeks post-partum elicited parental intent regarding the return or non-return of the reply form, and attitudes and knowledge about data linkage, vaccine safety, consent preferences and vaccination practices. Enrolment began in July 2009 and 1,129 households were recruited in a three-month period. Analysis has not yet been undertaken. The participation rate and selection bias for each method of consent will be compared when the data are analysed. Discussion: The VALiD RCT represents the first trial of opt-in versus opt-out consent for a data linkage study that assesses consent preferences and intent compared with actual opting in or opting out behaviour, and socioeconomic factors. The limitations to generalisability are discussed.Jesia G Berry, Philip Ryan, Annette J Braunack-Mayer, Katherine M Duszynski, Vicki Xafis, Michael S Gold, the Vaccine Assessment Using Linked Data (VALiD) Working Grou

Functional Relationship between Skull Form and Feeding Mechanics in Sphenodon, and Implications for Diapsid Skull Development

The vertebrate skull evolved to protect the brain and sense organs, but with the appearance of jaws and associated forces there was a remarkable structural diversification. This suggests that the evolution of skull form may be linked to these forces, but an important area of debate is whether bone in the skull is minimised with respect to these forces, or whether skulls are mechanically “over-designed” and constrained by phylogeny and development. Mechanical analysis of diapsid reptile skulls could shed light on this longstanding debate. Compared to those of mammals, the skulls of many extant and extinct diapsids comprise an open framework of fenestrae (window-like openings) separated by bony struts (e.g., lizards, tuatara, dinosaurs and crocodiles), a cranial form thought to be strongly linked to feeding forces. We investigated this link by utilising the powerful engineering approach of multibody dynamics analysis to predict the physiological forces acting on the skull of the diapsid reptile Sphenodon. We then ran a series of structural finite element analyses to assess the correlation between bone strain and skull form. With comprehensive loading we found that the distribution of peak von Mises strains was particularly uniform throughout the skull, although specific regions were dominated by tensile strains while others were dominated by compressive strains. Our analyses suggest that the frame-like skulls of diapsid reptiles are probably optimally formed (mechanically ideal: sufficient strength with the minimal amount of bone) with respect to functional forces; they are efficient in terms of having minimal bone volume, minimal weight, and also minimal energy demands in maintenance