Sample size re-estimation in paired comparative diagnostic accuracy studies with a binary response.

BACKGROUND: The sample size required to power a study to a nominal level in a paired comparative diagnostic accuracy study, i.e. studies in which the diagnostic accuracy of two testing procedures is compared relative to a gold standard, depends on the conditional dependence between the two tests - the lower the dependence the greater the sample size required. A priori, we usually do not know the dependence between the two tests and thus cannot determine the exact sample size required. One option is to use the implied sample size for the maximal negative dependence, giving the largest possible sample size. However, this is potentially wasteful of resources and unnecessarily burdensome on study participants as the study is likely to be overpowered. A more accurate estimate of the sample size can be determined at a planned interim analysis point where the sample size is re-estimated. METHODS: This paper discusses a sample size estimation and re-estimation method based on the maximum likelihood estimates, under an implied multinomial model, of the observed values of conditional dependence between the two tests and, if required, prevalence, at a planned interim. The method is illustrated by comparing the accuracy of two procedures for the detection of pancreatic cancer, one procedure using the standard battery of tests, and the other using the standard battery with the addition of a PET/CT scan all relative to the gold standard of a cell biopsy. Simulation of the proposed method illustrates its robustness under various conditions. RESULTS: The results show that the type I error rate of the overall experiment is stable using our suggested method and that the type II error rate is close to or above nominal. Furthermore, the instances in which the type II error rate is above nominal are in the situations where the lowest sample size is required, meaning a lower impact on the actual number of participants recruited. CONCLUSION: We recommend multinomial model maximum likelihood estimation of the conditional dependence between paired diagnostic accuracy tests at an interim to reduce the number of participants required to power the study to at least the nominal level. TRIAL REGISTRATION: ISRCTN ISRCTN73852054 . Registered 9th of January 2015. Retrospectively registered.

Development and psychometric testing of the online Adolescent Diabetes Needs Assessment Tool (ADNAT).

AIM: To report on the development and psychometric testing of the Adolescent Diabetes Needs Assessment Tool. BACKGROUND: The UK has the fifth largest paediatric diabetes population in the world, but one of the poorest levels of diabetes control, highlighting the need for intervention development. DESIGN: Mixed methods following recommendations for questionnaire design and validation. METHODS: A total of 171 young people (12-18 years) participated between 2008- 2011. Methods included item selection using secondary framework analysis, item review, pre-testing, piloting and online transfer. Statistical tests assessed reliability using item-total correlations, interitem consistency and test-retest reliability; and validity using blood glucose (HbA1c) levels and the Self-Management of type 1 Diabetes in Adolescence questionnaire. RESULTS: The Adolescent Diabetes Needs Assessment Tool consists of 117 questions divided between six domains of educational and psychosocial support needs. It combines reflective questioning with needs assessment to raise self-awareness to support adolescent decision-making in relation to diabetes self-care. Thirty-six of the questions provide self-care and psychosocial health assessment scores. Face and content validity of the scoring items were all positively evaluated in terms of appropriateness and readability and tests for validity found significant correlations with Self-Management of type 1 Diabetes in Adolescence and weak correlation with HbA1c , which compared favourably with Self-Management of type 1 Diabetes in Adolescence, the only comparable (USA) tool. Item response analysis validated the use of simple additive scores. CONCLUSIONS: The Adolescent Diabetes Needs Assessment Tool combines reflective learning with needs assessment to support patient-centred clinical consultations.

Development and preliminary validation of the challenges of living with cystic fibrosis (CLCF) questionnaire: a 46-item measure of treatment burden for parent/carers of children with CF.

OBJECTIVE: Treatments for cystic fibrosis (CF) are complex, labour-intensive, and perceived as highly burdensome by caregivers of children with CF. An instrument assessing burden of care is needed. DESIGN: A stepwise, qualitative design was used to create the CLCF with caregiver focus groups, participant researchers, a multidisciplinary professional panel, and cognitive interviews. MAIN OUTCOME MEASURES: Preliminary psychometric analyses evaluated the reliability and convergent validity of the CLCF scores. Cronbach's alpha assessed internal consistency and t-tests examined test-retest reliability. Correlations measured convergence between the Treatment Burden scale of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and the CLCF. Discriminant validity was assessed by comparing CLCF scores in one vs two-parent families, across ages, and in children with vs without Pseudomonas aeruginosa (PA). RESULTS: Six Challenge subscales emerged from the qualitative data and the professional panel constructed a scoresheet estimating the Time and Effort required for treatments. Internal consistency and test-retest reliability were adequate. Good convergence was found between the Total Challenge score and Treatment Burden on the CFQ-R (r=-0.49, p = 0.02, n = 31). A recent PA infection signalled higher Total Challenge for caregivers (F(23)11.72, p = 0.002). CONCLUSIONS: The CLCF, developed in partnership with parents/caregivers and CF professionals, is a timely, disease-specific burden measure for clinical research.

Pilot and feasibility studies: extending the conceptual framework.

In 2016, we published a conceptual framework outlining the conclusions of our work in defining pilot and feasibility studies. Since then, the CONSORT extension to randomised pilot and feasibility trials has been published and there have been further developments in the pilot study landscape. In this paper, we revisit and extend our framework to incorporate the various feasibility pathways open to researchers, which include internal pilot studies. We consider, with examples, when different approaches to feasibility and pilot studies are more effective and efficient, taking into account the pragmatic decisions that may need to be made. The ethical issues involved in pilot studies are discussed. We end with a consideration of the funders' perspective in making difficult resource decisions to include feasibility work and the policy implications of these; throughout, we provide examples of the uncertainties and compromises that researchers have to navigate to make progress in the most efficient way.

Development and validation of a short form psychometric tool assessing the caregiving Challenge of Living with Cystic Fibrosis (CLCF-SF) in a child.

OBJECTIVE: Caring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use. DESIGN: A novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families. MAIN OUTCOME MEASURES: Internal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity. RESULTS: The 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (r = 0.48) and child treatment management (r = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5, p < 0.001), and recent or no hospital admission (MD 3.6, 95%CI 0.25-6.95, p = 0.039). CONCLUSION: The CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF.

A population-based investigation of behavioural and emotional problems and maternal mental health: associations with autism spectrum disorder and intellectual disability.

BACKGROUND: While research indicates elevated behavioural and emotional problems in children with autism spectrum disorders (ASD) and decreased well-being in their parents, studies do not typically separate out the contribution of ASD from that of associated intellectual disabilities (ID). We investigated child behavioural and emotional problems, and maternal mental health, among cases with and without ASD and ID in a large population-representative sample. METHODS: Cross-sectional comparison of child behavioural and emotional problems and maternal mental health measures among 18,415 children (5 to 16 years old), of whom 47 had an ASD, 51 combined ASD with ID, 590 had only ID, and the remainder were the comparison group with no ASD or ID. RESULTS: The prevalence of likely clinical levels of behavioural and emotional problems was highest among children with ASD (with and without ID). After controlling for age, gender, adversity, and maternal mental health, the presence of ASD and ID significantly and independently increased the odds for hyperactivity symptoms, conduct, and emotional problems. Emotional disorder was more prevalent in mothers of children with ASD (with or without ID). The presence of ASD, but not ID, significantly increased the odds for maternal emotional disorder. As has been found in previous research, positive maternal mental health was not affected by the presence of ASD or ID. CONCLUSIONS: ASD and ID are independent risk factors for behavioural and emotional problems. ASD (but not ID) is positively associated with maternal emotional disorder. Approaches to diagnosing hyperactivity and conduct problems in children with ASD may need to be reconsidered.

Accounting for bias due to a non-ignorable tracing mechanism in a retrospective breast cancer cohort study.

We consider the analysis of competing risks in a retrospective breast cancer cohort study where tracing of patients is dependent on survival to a pre-specified truncation time. We demonstrate that if ignored, the observed cause-specific hazards will become distorted before the truncation time. Two approaches to account for the tracing bias are considered. First, a likelihood-based method using piecewise constant transition intensities under a Markov assumption. Second, a pseudo-likelihood method using inverse probability of tracing weights. For the breast cancer example, both methods improve the precision of estimates compared with a conventional approach based on excluding patients.

Pilot and feasibility studies for pragmatic trials have unique considerations and areas of uncertainty.

BACKGROUND AND OBJECTIVE: Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial. RESULTS: We identified ten relevant domains, partly based on the pragmatic-explanatory continuum indicator summary-2 (PRECIS-2) framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organization, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study. CONCLUSION: Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials.

Progression from external pilot to definitive randomised controlled trial: a methodological review of progression criteria reporting.

OBJECTIVES: Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports. STUDY DESIGN: Methodological review. METHODS: We searched four journals through PubMed: British Medical Journal Open, Pilot and Feasibility Studies, Trials and Public Library of Science One. Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics. RESULTS: We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified. CONCLUSIONS: Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial.

Transparency of informed consent in pilot and feasibility studies is inadequate: a single-center quality assurance study.

BACKGROUND: Pilot and feasibility studies (PAFS) often have complex objectives aimed at assessing feasibility of conducting a larger study. These may not be clear to participants in pilot studies. METHODS: Here, we aimed to assess the transparency of informed consent in PAFS by investigating whether researchers communicate, through patient information leaflets and consent forms, key features of the studies. We collected this data from original versions of these documents submitted for ethics approval and the final approved documents for PAFS submitted to the Hamilton Integrated Research Ethics Board, Canada. RESULTS: One hundred eighty-four PAFS, submitted for ethics approval from 2004 to 2020, were included, and we found that of the approved consent documents which were provided to participants, 83.2% (153) stated the terms "pilot" or "feasibility" in their title, 12% (22) stated the definition of a pilot/feasibility study, 42.4% (78) of the studies stated their intent to assess feasibility, 19.6% (36) stated the specific feasibility objectives, 1.6% (3) stated the criteria for success of the pilot study, and 0.5% (1) stated all five of these criteria. After ethics review, a small increase in transparency occurred, ranging from 1.6 to 2.8% depending on the criteria. By extracting data from the protocols of the PAFS, we found that 73.9% (136) stated intent to assess feasibility, 71.2% (131) stated specific feasibility objectives, and 33.7% (62) stated criteria for success of the study to lead to a larger study. CONCLUSION: The transparency of informed consent in PAFS is inadequate and needs to be specifically addressed by research ethics guidelines. Research ethics boards and researchers ought to be made aware and mindful of best practices of informed consent in the context of PAFS.

The Malawi Developmental Assessment Tool (MDAT): the creation, validation, and reliability of a tool to assess child development in rural African settings.

BACKGROUND: Although 80% of children with disabilities live in developing countries, there are few culturally appropriate developmental assessment tools available for these settings. Often tools from the West provide misleading findings in different cultural settings, where some items are unfamiliar and reference values are different from those of Western populations. METHODS AND FINDINGS: Following preliminary and qualitative studies, we produced a draft developmental assessment tool with 162 items in four domains of development. After face and content validity testing and piloting, we expanded the draft tool to 185 items. We then assessed 1,426 normal rural children aged 0-6 y from rural Malawi and derived age-standardized norms for all items. We examined performance of items using logistic regression and reliability using kappa statistics. We then considered all items at a consensus meeting and removed those performing badly and those that were unnecessary or difficult to administer, leaving 136 items in the final Malawi Developmental Assessment Tool (MDAT). We validated the tool by comparing age-matched normal children with those with malnutrition (120) and neurodisabilities (80). Reliability was good for items remaining with 94%-100% of items scoring kappas >0.4 for interobserver immediate, delayed, and intra-observer testing. We demonstrated significant differences in overall mean scores (and individual domain scores) for children with neurodisabilities (35 versus 99 [p<0.001]) when compared to normal children. Using a pass/fail technique similar to the Denver II, 3% of children with neurodisabilities passed in comparison to 82% of normal children, demonstrating good sensitivity (97%) and specificity (82%). Overall mean scores of children with malnutrition (weight for height <80%) were also significantly different from scores of normal controls (62.5 versus 77.4 [p<0.001]); scores in the separate domains, excluding social development, also differed between malnourished children and controls. In terms of pass/fail, 28% of malnourished children versus 94% of controls passed the test overall. CONCLUSIONS: A culturally relevant developmental assessment tool, the MDAT, has been created for use in African settings and shows good reliability, validity, and sensitivity for identification of children with neurodisabilities.

What is a pilot or feasibility study? A review of current practice and editorial policy.

BACKGROUND: In 2004, a review of pilot studies published in seven major medical journals during 2000-01 recommended that the statistical analysis of such studies should be either mainly descriptive or focus on sample size estimation, while results from hypothesis testing must be interpreted with caution. We revisited these journals to see whether the subsequent recommendations have changed the practice of reporting pilot studies. We also conducted a survey to identify the methodological components in registered research studies which are described as 'pilot' or 'feasibility' studies. We extended this survey to grant-awarding bodies and editors of medical journals to discover their policies regarding the function and reporting of pilot studies. METHODS: Papers from 2007-08 in seven medical journals were screened to retrieve published pilot studies. Reports of registered and completed studies on the UK Clinical Research Network (UKCRN) Portfolio database were retrieved and scrutinized. Guidance on the conduct and reporting of pilot studies was retrieved from the websites of three grant giving bodies and seven journal editors were canvassed. RESULTS: 54 pilot or feasibility studies published in 2007-8 were found, of which 26 (48%) were pilot studies of interventions and the remainder feasibility studies. The majority incorporated hypothesis-testing (81%), a control arm (69%) and a randomization procedure (62%). Most (81%) pointed towards the need for further research. Only 8 out of 90 pilot studies identified by the earlier review led to subsequent main studies. Twelve studies which were interventional pilot/feasibility studies and which included testing of some component of the research process were identified through the UKCRN Portfolio database. There was no clear distinction in use of the terms 'pilot' and 'feasibility'. Five journal editors replied to our entreaty. In general they were loathe to publish studies described as 'pilot'. CONCLUSION: Pilot studies are still poorly reported, with inappropriate emphasis on hypothesis-testing. Authors should be aware of the different requirements of pilot studies, feasibility studies and main studies and report them appropriately. Authors should be explicit as to the purpose of a pilot study. The definitions of feasibility and pilot studies vary and we make proposals here to clarify terminology.

Assessing the transparency of informed consent in feasibility and pilot studies: a single-centre quality assurance study protocol.

INTRODUCTION: Pilot/feasibility studies assess the feasibility of conducting a larger study. Although researchers ought to communicate the feasibility objectives to their participants, many research ethics guidelines do not comment on how informed consent applies to pilot studies. It is unclear whether researchers and research ethics boards clearly communicate the purpose of pilot studies to participants consenting.The primary objective of this study is to assess whether pilot/feasibility studies submitted for ethics approval to a research ethics board transparently communicate the purpose of the study to participants through their informed consent practice. A highly transparent consent practice entails the consent documents communicate: (1) the term 'pilot' or 'feasibility' in the title; (2) the definition of a pilot/feasibility study; (3) the primary objectives of the study are to assess feasibility; (4) the specific feasibility objectives; and (5) the criteria for the study to successfully lead to the main study. The secondary objectives are to assess whether there is a difference between submitted and revised versions of the consent documents (revisions are made to obtain research ethics approval), to determine factors associated with transparent consent practices and to assess the consistency with which pilot and feasibility studies assess feasibility outcomes as their primary objectives. METHODS AND ANALYSIS: This is a retrospective review of informed consent information for pilot/feasibility studies submitted to the Hamilton integrated Research Ethics Board, Canada. We will look at submitted and revised consent documents for pilot/feasibility studies submitted over a 14-year period. We will use descriptive statistics to summarise data, reporting results as percentages with 95% CIs, and conduct logistic regression to determine characteristics associated with transparent consent practices. ETHICS AND DISSEMINATION: The study protocol was approved by the Hamilton integrated Research Ethics Board, and the results of this study will be submitted for publication in a peer-reviewed journal.

Guidelines for reporting non-randomised pilot and feasibility studies.

As the number of submissions to Pilot and Feasibility Studies increases, there is a need for good quality reporting guidelines to help researchers tailor their reports in a way that is consistent and helpful to other readers. The publication in 2016 of the CONSORT extension to pilot and feasibility trials filled a much-needed gap, but there still remains some uncertainty as to how to report pilot and feasibility studies that are not randomised. This editorial aims to provide some general guidance on how to report the most common types of non-randomised pilot and feasibility studies that are submitted to the journal. We recommend using the CONSORT extension to pilot and feasibility trials as the main reference document-it includes detailed elaboration and explanation of each item, and in most cases, simple adaptation, or non-use of items that are not applicable, will suffice. Several checklists found on the Equator website may provide helpful supplementary guidance, when used alongside the CONSORT extension, and we give some examples.

A mixed methods study to evaluate the feasibility of using the Adolescent Diabetes Needs Assessment Tool App in paediatric diabetes care in preparation for a longitudinal cohort study.

BACKGROUND: An evaluation study was carried out to determine the feasibility of integrating the Adolescent Diabetes Needs Assessment Tool (ADNAT) App into UK paediatric diabetes care, to ascertain best practice standards and to determine methodological recommendations for a future cohort study. METHODS: A non-randomised, cohort, mixed methods study design was used to ensure equality of access to ADNAT for all participants at three sites in the North West of England. Following UK Medical Research Council guidance, the RE-AIM (reach, effectiveness (potential and perceived), adoption, implementation, maintenance) framework was used to guide study objectives and feasibility outcomes. Patients who completed ADNAT (completers) were compared with those who failed to complete (non-completers). Patients' glycaemic control (HbA1c) was accessed from their clinical data at baseline and at 6 months, alongside their ADNAT scores which were correlated with changes in HbA1c levels. The diabetes teams (respondents) completed a web-based survey and attended focus group interviews. RESULTS: Eighty-nine patients were recruited. Withdrawal rates were low at 4.5% (n = 4). Forty-four patients (49.4%) completed ADNAT, leaving 45 (50.6%) non-completers. There were large baseline differences in HbA1c and variable rates of change at 6 months. After adjusting for baseline HbA1C and site in an analysis of covariance, completers had a lower post-ADNAT mean HbA1C level than non-completers at 6 months (-5.42 mmol/mol, 95% CI -11.48, 0.64). Patients' glycaemic control (HbA1c) at 6 months correlated reasonably well with their ADNAT scores (Spearman's rho = 0.46). Survey and focus group data showed that ADNAT was judged to be an effective clinical tool by the diabetes teams. Value to patients was perceived by the teams to be linked to parental support, age and previous diabetes education. The combined data triangulated. It served to capture different dimensions which were used to define changes to achieve practice standards and methodological recommendations. CONCLUSIONS: The combined data showed that ADNAT has the potential to be a clinically viable tool. It has demonstrated the need for a randomised design that is tailored for a 'hard to reach' adolescent population. A cluster randomised controlled trial that involves sequential but random rollout of ADNAT over multiple time periods may be the most appropriate and is currently being considered for the larger study. TRIAL REGISTRATION: NIHR Children's Clinical Research Network, UKCRN ID 6633.

Pilot trials in physical activity journals: a review of reporting and editorial policy.

BACKGROUND: Since the early 2000s, a number of publications in the medical literature have highlighted inadequacies in the design, conduct and reporting of pilot trials. This work led to two notable publications in 2016: a conceptual framework for defining feasibility studies and an extension to the CONSORT 2010 statement to include pilot trials. It was hoped that these publications would educate researchers, leading to better use of pilot trials and thus more rigorously planned and informed randomised controlled trials. The aim of the present work is to evaluate the impact of these publications in the field of physical activity by reviewing the literature pre- and post-2016. This first article presents the pre-2016 review of the reporting and the current editorial policy applied to pilot trials published in physical activity journals. METHODS: Fourteen physical activity journals were screened for pilot and feasibility studies published between 2012 and 2015. The CONSORT 2010 extension to pilot and feasibility studies was used as a framework to assess the reporting quality of the studies. Editors of the eligible physical activity journals were canvassed regarding their editorial policy for pilot and feasibility studies. RESULTS: Thirty-one articles across five journals met the eligibility criteria. These articles fell into three distinct categories: trials that were carried out in preparation for a future definitive trial (23%), trials that evaluated the feasibility of a novel intervention but did not explicitly address a future definitive trial (23%) and trials that did not have any clear objectives to address feasibility (55%). Editors from all five journals stated that they generally do not accept pilot trials, and none gave reference to the CONSORT 2010 extension as a guideline for submissions. CONCLUSION: The result that over half of the studies did not have feasibility objectives is in line with previous research findings, demonstrating that these findings are not being disseminated effectively to researchers in the field of physical activity. The low standard of reporting across most reviewed articles and the neglect of the extended CONSORT 2010 statement by the journal editors highlight the need to actively disseminate these guidelines to ensure their impact.

Creation of the WHO Indicators of Infant and Young Child Development (IYCD): metadata synthesis across 10 countries.

BACKGROUND: Renewed global commitment to the improvement of early child development outcomes, as evidenced by the focus of the United Nations Sustainable Development Goal 4, highlights an increased need for reliable and valid measures to evaluate preventive and interventional efforts designed to affect change. Our objective was to create a new tool, applicable across multicultures, to measure development from 0 to 3 years through metadata synthesis. METHODS: Fourteen cross-sectional data sets were contributed on 21 083 children from 10 low/middle-income countries (LMIC), assessed using seven different tools (caregiver reported or directly assessed). Item groups, measuring similar developmental skills, were identified by item mapping across tools. Logistic regression curves displayed developmental trajectories for item groups across countries and age. Following expert consensus to identify well-performing items across developmental domains, a second mapping exercise was conducted to fill any gaps across the age range. The first version of the tool was constructed. Item response analysis validated our approach by putting all data sets onto a common scale. RESULTS: 789 individual items were identified across tools in the first mapping and 129 item groups selected for analysis. 70 item groups were then selected through consensus, based on statistical performance and perceived importance, with a further 50 items identified at second mapping. A tool comprising 120 items (23 fine motor, 23 gross motor, 20 receptive language, 24 expressive language, 30 socioemotional) was created. The linked data sets on a common scale showed a curvilinear trajectory of child development, highlighting the validity of our approach through excellent coverage by age and consistency of measurement across contributed tools, a novel finding in itself. CONCLUSIONS: We have created the first version of a prototype tool for measuring children in the early years, developed using novel easy to apply methodology; now it needs to be feasibility tested and piloted across several LMICs.

Parental depression following the early diagnosis of cystic fibrosis: a matched, prospective study.

OBJECTIVE: To assess risks for parental depression following the diagnosis of cystic fibrosis (CF) in a child. STUDY DESIGN: Matched cohort study in NW England; 45 parental couples with a child diagnosed with CF were compared with 45 control couples matching for age, sex, and position in the family of the index child. The Beck Depression Inventory (BDI-II) with a clinical cut-off > or = 13 for dysphoria (mild depression) was the main outcome. A stratified analysis was conducted using the Mantel-Haenszel risk-ratio estimator (RR(MH)) with eight strata for each of the matching variable combinations. RESULTS: Heterogeneity was found within the dataset. Parents with a child with CF < or = 9 months of age at baseline had an elevated prospective risk of depression (mothers RR(MH) [95% confidence interval (CI)] = 2.6[1.05,6.42], fathers RR(MH) [95%CI] = 2.26 [0.97,5.28]). The absence of a group effect for depression at follow-up after adjusting for the matching (mothers RR(MH) [95%CI] = 1.1 [0.59,2.05], fathers RR(MH) [95%CI] = 1.42 [0.66,3.08]) masked this heterogeneity. CONCLUSION: This hypothesis-generating finding suggests that parents may be more vulnerable to depression when their child is diagnosed with a life-shortening condition during the first few months of life. Mood in parents of infants diagnosed early needs to be monitored longitudinally and preventative strategies devised.

Design of a clustered observational study to predict emergency admissions in the elderly: statistical reasoning in clinical practice.

OBJECTIVE: To describe the statistical design issues and practical considerations that had to be addressed in setting up a clustered observational study of emergency admission to hospital of elderly people. STUDY DESIGN AND SETTING: Clustered observational study (sample survey) of elderly people registered with 18 general practices in Halton Primary Care Trust in the north-west of England. RESULTS: The statistical design features that warranted particular attention were sample size determination, intra-class correlation, sampling and recruitment, bias and confounding. Pragmatic decisions based on derived scenarios of different design effects are discussed. A pilot study was carried out in one practice. From the remaining practices, a total of 4000 people were sampled, stratified by gender. The average cluster size was 200 and the intra-class correlation coefficient for the emergency admission outcome was 0.00034, 95% confidence interval (0-0.008). CONCLUSION: Studies that involve sampling from clusters of people are common in a wide range of healthcare settings. The clustering adds an extra level of complexity to the study design. This study provides an empirical illustration of the importance of statistical as well as clinical reasoning in study design in clinical practice.

Breast asymmetry and predisposition to breast cancer.

INTRODUCTION: It has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. METHODS: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy controls who had remained disease-free to time of the present study. The study group consisted of 252 asymptomatic women who had normal mammography, but went on to develop breast cancer. The control group were 252 age-matched healthy controls whose mammograms were also normal and who remained free of cancer during the study period. Breast volume was calculated from the cranio-caudal mammograms for each group, and the relationships between asymmetry, established risk factors and the presence or absence of breast cancer were explored. RESULTS: The group who went on to develop breast cancer had higher breast asymmetry than controls (absolute asymmetry odds ratio 1.50 per 100 ml, confidence interval (CI) 1.10, 2.04; relative asymmetry 1.09, CI 1.01, 1.18), increased incidence of family history of breast cancer, lower age at menarche, later menopause, later first pregnancies and a higher frequency of high risk breast parenchyma types. Conditional logistic regression analysis showed that breast asymmetry, height, family history of breast cancer, age at menarche, parenchyma type and menopausal status were significant independent predictors of breast cancer. When age at menopause was included in the model for the subgroup of post-menopausal women, absolute breast fluctuating asymmetry (FA) and relative breast FA remained significant effects. CONCLUSION: Breast asymmetry was greater in healthy women who later developed breast cancer than in women who did not.