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1.  Scoping review of patient- and family-oriented outcomes and measures for chronic pediatric disease 
BMC Pediatrics  2015;15:7.
Background
Improvements in health care for children with chronic diseases must be informed by research that emphasizes outcomes of importance to patients and families. To support a program of research in the field of rare inborn errors of metabolism (IEM), we conducted a broad scoping review of primary studies that: (i) focused on chronic pediatric diseases similar to IEM in etiology or manifestations and in complexity of management; (ii) reported patient- and/or family-oriented outcomes; and (iii) measured these outcomes using self-administered tools.
Methods
We developed a comprehensive review protocol and implemented an electronic search strategy to identify relevant citations in Medline, EMBASE, DARE and Cochrane. Two reviewers applied pre-specified criteria to titles/abstracts using a liberal accelerated approach. Articles eligible for full-text review were screened by two independent reviewers with discrepancies resolved by consensus. One researcher abstracted data on study characteristics, patient- and family-oriented outcomes, and self-administered measures. Data were validated by a second researcher.
Results
4,118 citations were screened with 304 articles included. Across all included reports, the most-represented diseases were diabetes (35%), cerebral palsy (23%) and epilepsy (18%). We identified 43 unique patient- and family-oriented outcomes from among five emergent domains, with mental health outcomes appearing most frequently. The studies reported the use of 405 independent self-administered measures of these outcomes.
Conclusions
Patient- and family-oriented research investigating chronic pediatric diseases emphasizes mental health and appears to be relatively well-developed in the diabetes literature. Future research can build on this foundation while identifying additional outcomes that are priorities for patients and families.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-015-0323-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12887-015-0323-x
PMCID: PMC4334411
Patient-centered outcomes research; Patient-centered care; Outcomes research; Outcome measures; Metabolism; Inborn errors; Assessment; Patient outcomes; Rare diseases; Family-centered care
2.  Measuring the psychosocial burden in women with low-grade abnormal cervical cytology in the TOMBOLA trial: psychometric properties of the Process and Outcome Specific Measure (POSM) 
Background
There is a need for an instrument to measure the psychosocial burden of receiving an abnormal cervical cytology result which can be used regardless of the clinical management women receive.
Methods
3331 women completed the POSM as part of baseline psychosocial assessment in a trial of management of low grade cervical cytological abnormalities. Factor analysis and reliability assessment of the POSM were conducted.
Results
Two factors were extracted from the POSM: Factor 1, containing items related to worry; and Factor 2 containing items relating to satisfaction with information and support received and change in the way women felt about themselves. Factor 1 had good reliability (Cronbach’s alpha 0.769), however reliability of the Factor 2 was poorer (0.482). Data collected at four subsequent time points demonstrated that the factor structure was stable over time.
Conclusion
This study demonstrates the presence and reliability of a scale measuring worries within the POSM. This analysis will inform its future use in this population and in other related contexts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12955-014-0154-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12955-014-0154-8
PMCID: PMC4252018
Cervical intraepithelial neoplasia; Questionnaires; Factor analysis; Psychosocial distress
3.  A Qualitative Study of Provider Perspectives of Structural Barriers to Cervical Cancer Screening Among First Nations Women 
Objective
In Canada, opportunistic screening programs have successfully reduced mortality from cervical cancer; however, minority or disadvantaged groups, as well as women in northern and rural areas, are inadequately recruited by this approach. Hence, we set out to examine the structural barriers that prevent First Nations women’s participation in cervical cancer screening.
Methods
Using a participatory action research approach and semistructured interview guides, we conducted in-depth interviews with 18 experienced health care professionals, 12 of whom were also community members. These individuals included nurses, nurse practitioners, community health representatives, social workers and physicians who provide care to women in our First Nations partner communities. In the current report, we explored perceived barriers to cervical cancer screening through the lens of service providers.
Results
Structural barriers to cervical cancer screening for First Nations women included shortage of appropriate health care providers, lack of a recall-based screening system, geographic and transportation barriers; health literacy and socioeconomic inequalities, generational effects, and the colonial legacy.
Conclusion
Existing, opportunistic cervical cancer screening programs do not perform well for First Nations women who experience significant screening-related health inequalities that are largely influenced by structural barriers. Sustainable screening interventions in First Nations communities require approaches that resolve these structural barriers, explore new ways of screening, and provide education for both women and health care providers. Many of the structural barriers are rooted in colonial history. Given the negative impact of the consequences of colonization on indigenous women worldwide, many of our findings strongly resonate with marginalized populations in other countries.
doi:10.1016/j.whi.2013.06.005
PMCID: PMC4111655  PMID: 23993479 CAMSID: cams4547
4.  Relationship Between Adiposity and Pulmonary Function in School-Aged Canadian Children 
Reduced lung function has been observed in adults with excess adiposity; however, in children, the relationship between adiposity and lung function is not clearly understood. A sample of 1,583 children, less than 18 years of age, from the Canadian Health Measures Survey (CHMS) was used to examine the associations of various anthropometric and skinfold measures with lung function parameters. The mean age of the sample was 12.15 (0.096). In normal weight boys, body mass index (BMI) was positively associated with forced vital capacity (FVC), FEV0.75 and FEV1; while in overweight or obese boys, waist circumference (WC) and waist-to-hip ratio showed inverse correlations with pulmonary function measures. Similarly, in normal weight girls, BMI and WC had positive associations with lung function measures but no inverse effect of adiposity was observed in overweight or obese girls. Skinfold analysis showed that only triceps skinfold had a significant inverse association with FVC and borderline significant associations with FEV0.75 and FEV1 in normal weight boys; while in overweight or obese boys, all the skinfold indicators displayed inverse correlations with lung function. The best predictor of lung function was triceps skinfold with βstd=−0.3869 for FVC, −0.3496 for FEV0.75 and −0.3668 for FEV1. No inverse correlations between skinfolds and lung function were observed in girls. Adiposity had differing effects on respiratory function that were dependent on sex and BMI group with the most significant effect on the overweight or obese boys. The most important indicator of adiposity in boys with BMI <30 kg/m2 was triceps skinfold. In girls, adiposity was not associated with poor lung function.
doi:10.1089/ped.2014.0349
PMCID: PMC4170807  PMID: 25276486
5.  Intermediate CAG Repeat Expansion in the ATXN2 Gene Is a Unique Genetic Risk Factor for ALS−A Systematic Review and Meta-Analysis of Observational Studies 
PLoS ONE  2014;9(8):e105534.
Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30–33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91–6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58–8.17) and sporadic ALS cases (OR = 3.16, 1.88–5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.
doi:10.1371/journal.pone.0105534
PMCID: PMC4141758  PMID: 25148523
6.  Folic Acid Supplementation Use and the MTHFR C677T Polymorphism in Orofacial Clefts Etiology: An Individual Participant Data Pooled-Analysis 
Background
This study examines gene-environment interaction (GEI) between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled-analyticapproach on four studies that used similar methods.
Methods
We used logistic regression to analyse the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non-syndromic clefts lip or without cleft palate (CL(P)) and non syndromic cleft palate (CP)] and control groups.
Results
There was a reduced risk of CL(P) with maternal folic acid use (p=0.008; OR=0.70, 95% CI: 0.65–0.94) and with supplements containing folic acid (p=0.028, OR=0.80, 95% CI: 0.65–0.94). Maternal smoking increased the risk of both CL(P) (p<10e−3; OR=1.62, 95% CI: 1.35–1.95) and CP (p=0.028; OR=1.38, 95% CI: 1.04–1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes.
Conclusion
This individual paticipant data (IPD) meta-analysis affords greater statistical power and can help alleviate the problems associated with aggregate-level data-sharing. The result of this IPD meta-analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes.
doi:10.1002/bdra.23133
PMCID: PMC3745533  PMID: 23670871
Cleft lip and palate; MTHFR; Folic acid; Individual patient data; pooled-analysis
7.  Correction: Characterization of IGF-II Isoforms in Binge Eating Disorder and Its Group Psychological Treatment 
PLoS ONE  2014;9(1):10.1371/annotation/bb067823-48b8-4573-907e-224cb73917a2.
doi:10.1371/annotation/bb067823-48b8-4573-907e-224cb73917a2
PMCID: PMC3893313
8.  Using Community Engagement to Inform and Implement a Community-Randomized Controlled Trial in the Anishinaabek Cervical Cancer Screening Study 
Social, political, and economic factors are directly and indirectly associated with the quality and distribution of health resources across Canada. First Nations (FN) women in particular, endure a disproportionate burden of ill health in contrast to the mainstream population. The complex relationship of health, social, and historical determinants are inherent to increased cervical cancer in FN women. This can be traced back to the colonial oppression suffered by Canadian FN and the social inequalities they have since faced. Screening – the Papinacolaou (Pap) test – and early immunization have rendered cervical cancer almost entirely preventable but despite these options, FN women endure notably higher rates of diagnosis and mortality due to cervical cancer. The Anishinaabek Cervical Cancer Screening Study (ACCSS) is a participatory action research project investigating the factors underlying the cervical cancer burden in FN women. ACCSS is a collaboration with 11 FN communities in Northwest Ontario, Canada, and a multidisciplinary research team from across Canada with expertise in cancer biology, epidemiology, medical anthropology, public health, virology, women’s health, and pathology. Interviews with healthcare providers and community members revealed that prior to any formal data collection education must be offered. Consequently, an educational component was integrated into the existing quantitative design of the study: a two-armed, community-randomized trial that compares the uptake of two different cervical screening modalities. In ACCSS, the Research Team integrates community engagement and the flexible nature of participatory research with the scientific rigor of a randomized controlled trial. ACCSS findings will inform culturally appropriate screening strategies, aiming to reduce the disproportionate burden of cervical disease in concert with priorities of the partner FN communities.
doi:10.3389/fonc.2014.00027
PMCID: PMC3928568  PMID: 24600584
indigenous health; women’s health; social determinants of health disparities; community engagement; cervical screening
9.  Psychosocial Impact of Alternative Management Policies for Low-Grade Cervical Abnormalities: Results from the TOMBOLA Randomised Controlled Trial 
PLoS ONE  2013;8(12):e80092.
Background
Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination.
Methods
Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20–59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥8) and significant anxiety (≥11; “30-month percentages”). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance.
Results
There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80–1.21) or anxiety (OR = 0.97, 95% CI 0.81–1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38–0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54–0.84). Neither anxiety nor depression differed between arms at subsequent time-points.
Conclusions
There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost.
Trial Registration
Controlled-Trials.com ISRCTN 34841617
doi:10.1371/journal.pone.0080092
PMCID: PMC3875419  PMID: 24386076
10.  An international case-control study of adult diet and brain tumor risk: a histology-specific analysis by food group 
Annals of epidemiology  2009;19(3):10.1016/j.annepidem.2008.12.010.
PURPOSE
Existing studies of diet and adult brain tumors have been limited by small numbers in histology–specific subgroups. Dietary data from an international collaborative case-control study on adult brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups.
METHODS
The study included 1,548 cases diagnosed between 1984 and 1991 and 2,486 controls from 8 study centers in 6 countries. Of the 1,548 cases, 1,185 were gliomas, 332 were meningiomas, and 31 were other tumor types. Dietary consumption was measured as average g/day.
RESULTS
We found inverse associations between some vegetable groups and glioma risk, the strongest for yellow-orange vegetables (odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.5–0.9 for the 4th vs. 1st quartile of consumption, p for trend < 0.001), and the association was limited to specific glioma subtypes. There was no association with cured meat. Non-cured meat was associated with a modest increase in glioma risk (OR = 1.3, CI = 1.0–1.7 for 4th quartile vs. 1st quartile, p for trend = 0.01). We also found positive associations between egg, grain, and citrus fruit consumption and glioma but not meningioma risk.
CONCLUSIONS
Our study suggests that selected dietary food groups may be associated with adult gliomas and its subtypes, but not meningiomas.
doi:10.1016/j.annepidem.2008.12.010
PMCID: PMC3832293  PMID: 19216998
brain tumors; glioma; meningioma; diet; N-nitroso compounds; vegetables
12.  Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers 
Breast (Edinburgh, Scotland)  2010;19(6):479-483.
Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrolment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70–0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71–1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.
doi:10.1016/j.breast.2010.05.009
PMCID: PMC3756317  PMID: 20541936
BRCA1; BRCA2; Alcohol; Breast cancer; Case-control; Wine
13.  Primary care role in expanded newborn screening 
Canadian Family Physician  2013;59(8):861-868.
Abstract
Objective
To examine the role of primary care providers in informing and supporting families who receive positive screening results.
Design
Cross-sectional survey.
Setting
Ontario.
Participants
Family physicians, pediatricians, and midwives involved in newborn care.
Main outcome measures
Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns.
Results
A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening.
Conclusion
Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted.
PMCID: PMC3743702  PMID: 23946032
14.  Cancer Risk in Children and Adolescents with Birth Defects: A Population-Based Cohort Study 
PLoS ONE  2013;8(7):e69077.
Objective
Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects.
Methods and Findings
This retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus.
Conclusion
Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.
doi:10.1371/journal.pone.0069077
PMCID: PMC3714243  PMID: 23874873
15.  Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans 
We propose guidelines to evaluate the cumulative evidence of gene–environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.
doi:10.1093/ije/dys010
PMCID: PMC3481885  PMID: 22596931
Genetics; environment; interactions; evaluations
16.  Health-care providers' views on pursuing reproductive benefit through newborn screening: the case of sickle cell disorders 
Newborn screening (NBS) programs aim to identify affected infants before the onset of treatable disorders. Historically, benefits to the family and society were considered secondary to this clinical benefit; yet, recent discourse defending expanded NBS has argued that screening can in part be justified by secondary benefits, such as learning reproductive risk information to support family planning (‘reproductive benefit'). Despite increased attention to these secondary benefits of NBS, stakeholders' values remain unknown. We report a mixed methods study that included an examination of providers' views toward the pursuit of reproductive risk information through NBS, using sickle cell disorder carrier status as an example. We surveyed a stratified random sample of 1615 providers in Ontario, and interviewed 42 providers across 7 disciplines. A majority endorsed the identification of reproductive risks as a goal of NBS (74–77%). Providers' dominant rationale was that knowledge of carrier status is an important and inherent benefit of NBS as it allows people to make reproductive choices, which is consistent with the goals of disease prevention. However, some challenged its appropriateness, questioning its logic, timing and impact on disease prevention. Others were sensitive to intruding on individuals' choices or children's independent rights. While the dominant view is consistent with discourse defending expanded NBS, it deviates from the traditional screening principles that underpin most public health interventions. Broader discussion of the balance between benefits to screened individuals and those to families and societies, in the context of public health programs, is needed.
doi:10.1038/ejhg.2011.188
PMCID: PMC3330205  PMID: 22071888
newborn screening; reproductive risk information; stakeholder engagement; health policy; sick cell disorders; public health ethics
17.  Is rigorous retrospective harmonization possible? Application of the DataSHaPER approach across 53 large studies 
Background Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies.
Methods This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored.
Results Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized.
Conclusion The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.
doi:10.1093/ije/dyr106
PMCID: PMC3204208  PMID: 21804097
Data synthesis; data quality; data pooling; harmonization; meta-analysis; DataSHaPER; retrospective harmonization
18.  Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies 
Background
For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia.
Design and methods
Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling.
Discussion
Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.
doi:10.1186/1471-2288-12-116
PMCID: PMC3502117  PMID: 22862891
Genetic epidemiology; Melanoma; Meta-analysis; Pooled-analysis; Skin cancer; Study design
19.  After-effects reported by women having follow-up cervical cytology tests in primary care: a cohort study within the TOMBOLA trial 
The British Journal of General Practice  2011;61(587):e333-e339.
Background
Although it is recognised that some women experience pain or bleeding during a cervical cytology test, few studies have quantified physical after-effects of these tests.
Aim
To investigate the frequency, severity, and duration of after-effects in women undergoing follow-up cervical cytology tests, and to identify subgroups with higher frequencies in Grampian, Tayside, and Nottingham.
Design
Cohort study nested with a multi-centre individually randomised controlled trial.
Method
The cohort included 1120 women, aged 20–59 years, with low-grade abnormal cervical cytology who completed a baseline sociodemographic questionnaire and had a follow-up cervical cytology test in primary care 6 months later. Six weeks after this test, women completed a postal questionnaire on pain, bleeding, and discharge experienced after the test, including duration and severity. The adjusted prevalence of each after-effect was computed using logistic regression.
Results
A total of 884 women (79%) completed the after-effects questionnaire; 30% of women experienced one or more after-effect: 15% reported pain, 16% bleeding, and 7% discharge. The duration of discharge was ≤2 days for 66%, 3–6 days for 22%, and ≥7 days for 11% of women. Pain or bleeding lasted ≤2 days in more than 80% of women. Severe after-effects were reported by <1% of women. The prevalence of pain decreased with increasing age. Bleeding was more frequent among nulliparous women. Discharge was more common among oral contraceptive users.
Conclusion
Pain, bleeding, and discharge are not uncommon in women having follow-up cervical cytology tests. Informing women about possible after-effects could better prepare them and provide reassurance, thereby minimising potential non-adherence with follow-up or non-participation with screening in the future.
doi:10.3399/bjgp11X578007
PMCID: PMC3103696  PMID: 21801512
after-effects; bleeding; complications; cervical smears; cytology; pain; primary care; vaginal discharge
20.  Strengthening the Reporting of Genetic Risk Prediction Studies (GRIPS): Explanation and Elaboration 
European journal of epidemiology  2011;26(4):313-337.
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice.The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality.Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction.A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines.These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
doi:10.1007/s10654-011-9551-z
PMCID: PMC3088812  PMID: 21424820
21.  Study protocol: the empirical investigation of methods to correct for measurement error in biobanks with dietary assessment 
Background
The Public Population Project in Genomics (P3G) is an organisation that aims to promote collaboration between researchers in the field of population-based genomics. The main objectives of P3G are to encourage collaboration between researchers and biobankers, optimize study design, promote the harmonization of information use in biobanks, and facilitate transfer of knowledge between interested parties. The importance of calibration and harmonisation of methods for environmental exposure assessment to allow pooling of data across studies in the evaluation of gene-environment interactions has been recognised by P3G, which has set up a methodological group on calibration with the aim of; 1) reviewing the published methodological literature on measurement error correction methods with assumptions and methods of implementation; 2) reviewing the evidence available from published nutritional epidemiological studies that have used a calibration approach; 3) disseminating information in the form of a comparison chart on approaches to perform calibration studies and how to obtain correction factors in order to support research groups collaborating within the P3G network that are unfamiliar with the methods employed; 4) with application to the field of nutritional epidemiology, including gene-diet interactions, ultimately developing a inventory of the typical correction factors for various nutrients.
Methods/Design
Systematic review of (a) the methodological literature on methods to correct for measurement error in epidemiological studies; and (b) studies that have been designed primarily to investigate the association between diet and disease and have also corrected for measurement error in dietary intake.
Discussion
The conduct of a systematic review of the methodological literature on calibration will facilitate the evaluation of methods to correct for measurement error and the design of calibration studies for the prospective pooling of biobanks. This could increase the efficiency of the design of such studies, improve statistical power, reduce bias, and aid in the assessment of gene-environment interaction effects in complex diseases. The systematic review of calibration of dietary intake information could inform gene-diet interaction investigations involving the pooling of results from studies with nutritional data collected in different ways.
doi:10.1186/1471-2288-11-135
PMCID: PMC3198752  PMID: 21974830
22.  Strengthening the reporting of genetic risk prediction studies: the GRIPS statement 
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies, building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published on the EJHG website.
doi:10.1038/ejhg.2011.25
PMCID: PMC3172920  PMID: 21407265
23.  Human Papillomavirus Infection and Anxiety: Analyses in Women with Low-Grade Cervical Cytological Abnormalities Unaware of Their Infection Status 
PLoS ONE  2011;6(6):e21046.
Background
Women testing positive for human papillomavirus (HPV) infection experience increased levels of anxiety that have been attributed to fears of stigmatization and developing cervical cancer. The objective of this study was to investigate the association between HPV infection and anxiety in women who were unaware they had been tested specifically for HPV, to determine if any anxiety experienced by HPV-positive women could be due to causes other than learning of test results.
Methods
This study was nested within a randomised controlled trial of management of women with abnormal cervical cytology conducted in the United Kingdom with recruitment between 1999 and 2002. At baseline, prior to having a sample taken for HPV testing, the results of which were not disclosed, women were assessed for anxiety using the Hospital Anxiety and Depression Scale and asked about fears of developing cervical cancer (“cancer worries”); this assessment was repeated at 12, 18, 24, and 30 months of follow-up. Logistic regression and generalized estimating equations were used for the cross-sectional (baseline) and longitudinal analyses, respectively.
Results
Among the 2842 participants, there was no association between HPV status and anxiety among white women. Among non-white women, however, anxiety was less common among HPV-positive than HPV-negative women (adjusted odds ratio 0.41, 95% confidence interval 0.22 to 0.77). Among non-smokers, cancer worry was more common in HPV-positive than HPV-negative women; the opposite association was observed among ex-smokers.
Conclusions
Associations between HPV status and anxiety may be explained by factors other than learning of test results and may vary by ethnicity and lifestyle factors.
doi:10.1371/journal.pone.0021046
PMCID: PMC3116883  PMID: 21698168
24.  Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration 
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
doi:10.1038/ejhg.2011.27
PMCID: PMC3083630  PMID: 21407270
25.  Strengthening the reporting of genetic risk prediction studies: the GRIPS statement 
European Journal of Epidemiology  2011;26(4):255-259.
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published.
doi:10.1007/s10654-011-9552-y
PMCID: PMC3088799  PMID: 21431409
Genetic; Risk prediction; Methodology; Guidelines; Reporting

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