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Background: Printed educational materials (PEMs) have long been used to inform clinicians on evidence-based practices. However, the evidence for their effects on patient care and outcomes is unclear. In Ontario, despite widely available clinical practice guidelines recommending antihypertensives and cholesterol-lowering agents for patients with diabetes, prescriptions remain low. We aimed to determine whether PEMs can influence physicians to intensify prescribing of these medications., Methods: A pragmatic, 2 × 2 factorial, cluster randomized controlled trial was designed to ascertain the effect of two PEM formats on physician prescribing: a postcard-sized message ("outsert") or a longer narrative article ("insert"). Ontario family physician practices (clusters) were randomly allocated to receive the insert, outsert, both or neither. Physicians were eligible if they were in active practice and their patients were included if they were over 65 years with a diabetes diagnosis; both were unaware of the trial. Administrative databases at ICES (formerly the Institute for Clinical Evaluative Sciences) were used to link patients to their physician and to analyse prescribing patterns at baseline and 1 year following PEM mailout. The primary outcome was intensification defined as the addition of a new antihypertensive or cholesterol-lowering agent, or dose increase of a current drug, measured at the patient level. Analyses were by intention-to-treat and accounted for the clustering of patients to physicians., Results: We randomly assigned 4231 practices (39% of Ontario family physicians) with a total population of 185,526 patients (20% of patients with diabetes in Ontario primary care) to receive the insert, outsert, both, and neither; among these, 4118 practices were analysed (n = 1025, n = 1037, n = 1031, n = 1025, respectively). No significant treatment effect was found for the outsert (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.98 to 1.04) or the insert (OR 0.99, 95% CI 0.96 to 1.02). Percent of intensification in the four arms was similar (approximately 46%). Adjustment for physician characteristics (e.g., age, sex, practice location) had no impact on these findings., Conclusions: PEMs have no effect on physician's adherence to recommendations for the management of diabetes-related complications in Ontario. Further research should investigate the effect of other strategies to narrow this evidence-to-practice gap., Trial Registration: ISRCTN72772651 . Retrospectively registered 21 July 2005., (© 2021. The Author(s).)

Purpose: Immunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy., Methods: Both patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3 weeks (after cycle 1, chemotherapy alone) and 6 weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing., Results: ScRNA-seq analysis showed significant baseline heterogeneity of tumor-infiltrating immune cell populations between the two patients as well as modulation of the tumor microenvironment by chemotherapy and immunotherapy. In the responding patient there was a population of PD-1 high -expressing T cells which significantly decreased after nab-paclitaxel plus pembrolizumab treatment as well as a presence of tissue-resident memory T cells (T RM ). In contrast, tumors from the patient with rapid disease progression showed a prevalent and persistent myeloid compartment., Conclusions: Our study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor.

Background: Both inadequate sleep and internalizing problems, such as symptoms of anxiety and depression, are prevalent among adolescents with sparse epidemiological literature outlining sex-specific relationships at this critical age., Objective: To examine cross-sectional and prospective relationships between self-reported sleep problems, indicated by sleep duration, difficulties getting to sleep and changes in difficulties getting to sleep with internalizing problems in early adolescence., Methods: This study was a secondary analysis of data from the Canadian National Longitudinal Survey of Children and Youth. Multivariable linear regression was used to estimate cross-sectional and longitudinal associations. Relevant family and social context variables were controlled for in multivariable analyses. Family functioning was assessed as a potential effect modifier., Results: There were 993 and 736 participants [longitudinal cohort entry age of 10 or 11 years; 49% male] in longitudinal and cross-sectional analyses, respectively. Most cross-sectional multivariable analyses of sleep duration and internalizing problems revealed no statistical associations. Difficulties sleeping and concurrent internalizing problems were positively associated in 12/13 year old females (β = 1.77 [0.94, 2.61], R 2  = 17%) and males (β = 1.18 [0.36, 2.01], R 2  = 16%). High persistent difficulties sleeping in females aged 12/13 to 14/15 years also positively predicted internalizing problems in females age 14/15 years (β = 1.90 [0.52, 3.29], R 2  = 21%) while controlling for initial internalizing symptoms. Family functioning was not found to be an effect modifier., Conclusion: Findings highlight the potential role of difficulties sleeping for adolescents' mental health. Public health initiatives to promote sleep hygiene in this population subgroup are critical to prevent the potential long-term health impact of sleep problems., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Iron deficiency anemia, the largest cause of anemia worldwide, adversely affects cognitive development in children. Moreover, the imperceptible childhood anemia prevalence reduction in response to anemia control measures is associated with tremendous social and economic cost., Objective: To evaluate the effects of community-based parental education/counseling when combined with usual treatment on children's anemia cure rate., Design, Setting, and Participants: A pragmatic cluster randomized clinical trial in children aged 12 to 59 months from 55 villages from the rural Chamrajnagar district in southern India was conducted between November 2014 and July 2015; 6-month follow-up ended in January 2016. Villages were randomly assigned to either usual treatment (n = 27) or to the intervention (n = 28). Among 1144 participating children, 534 were diagnosed as having anemia (hemoglobin levels <11 g/dL and >7.9 g/dL; to convert to grams per liter, multiply by 10) and constituted the study sample in this analysis. Data were analyzed between July 2016 and September 2017., Interventions: Iron and folic acid (IFA), 20 mg/d, 5 times daily per week, for 5 months (usual treatment) or health worker-delivered education/counseling combined with usual treatment (intervention)., Main Outcomes and Measures: The primary outcome was anemia cure rate defined as hemoglobin level at or greater than 11 g/dL during follow-up., Results: Of the children included in the study, the mean age was 30 months, with a slightly higher ratio of boys to girls. Of 534 children with anemia (intervention n = 303; usual treatment n = 231), 517 were reassessed after 6 months (intervention n = 298; usual treatment n = 219) while 17 were lost to follow-up (intervention n = 5 and usual treatment n = 12). Anemia cure rate was higher in children in the intervention group compared with children receiving usual treatment (55.7% [n = 166 of 298] vs 41.4% [n = 90 of 219]). The risk ratio derived through multilevel logistic regression was 1.37 (95% CI, 1.04-1.70); the model-estimated risk difference was 15.1% (95% CI, 3.9-26.3). Intervention-group children demonstrated larger mean hemoglobin increments (difference, intervention vs control: 0.25 g/dL; 95% CI, 0.07-0.44 g/dL) and improved IFA adherence (61.7%; 95% CI, 56.2-67.3 vs 48.4%; 95% CI, 41.7-55.1 consumed >75% of tablets provided). Adverse events were mild (intervention: 26.8%; 95% CI, 21.8-31.9 vs usual treatment: 21%; 95% CI, 15.6-26.4). To cure 1 child with anemia, 7 mothers needed to be counseled (number needed to treat: 7; 95% CI, 4-26)., Conclusions and Relevance: Parental education and counseling by a community health worker achieved perceivable gains in curing childhood anemia. Policy makers should consider this approach to enhance population level anemia control., Trial Registration: ISRCTN identifier: ISRCTN68413407.

Background: Of women diagnosed with metastatic breast cancer (MBC), 20% to 30% survive ≥5 years. We evaluated data from a large breast cancer program to identify features associated with MBC survival., Patients and Methods: Women diagnosed with MBC in or after 1999 were included. Long-term MBC survival was defined as ≥5 years from date of MBC diagnosis (n = 122), short-term MBC survival as ≤2 years (n = 191). Differences were assessed using t tests, Wilcoxon-Mann-Whitney tests, χ 2 , and Fisher exact tests. Odds ratios (ORs) were calculated using multivariate logistic regression models., Results: Long-term survivors were significantly (P < .05) younger, premenopausal, partnered, had estrogen receptor (ER)-positive, progesterone receptor-positive, and HER2-positive disease, lower Charlson Comorbidity Index, lower rates of visceral metastases, and higher household income. After adjustment for potential confounders, de novo MBC, premenopausal status, ER-positive status, and HER2-positive status remained significantly positively associated with long-term survival (respectively: OR, 2.68 [95% confidence interval (CI), 1.48-4.88]; OR, 1.96 [95% CI, 1.02-3.79]; OR, 3.74 [95% CI, 1.72-8.14]; OR, 2.88 [95% CI, 1.61-5.14]). Triple-negative status, visceral with bone metastases, and brain metastases remained negatively associated with long-term survival (respectively: OR, 0.12 [95% CI, 0.05-0.29]; OR, 0.18 [95% CI, 0.07-0.47]; OR, 0.16 [95% CI, 0.04-0.60]). Partner status and household income were significant in univariate but not multivariate analyses., Conclusion: Diagnosis of de novo MBC, premenopausal status, ER-positive status, and HER2-positive status were positively associated whereas triple-negative status, brain metastases, and visceral with bone metastases were inversely associated with long-term survival. These findings can be applied to better prognosticate survival for MBC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate seasonal patterns of early inflammatory arthritis (IA) onset and potential associations with IA symptom onset., Methods: The Canadian Early Arthritis Cohort (CATCH) is an inception cohort study of adults with early (12 months or less) IA. We used patient reports of symptom onset as a proxy of IA onset and examined the seasonal distribution of IA onset over 10 years. Influenza time series was based on laboratory-confirmed influenza A and B from the Canadian FluWatch surveillance from 2010-2016. Bivariate analysis of influenza and IA was performed using cross-correlations with different time lags and Poisson regression. IA and influenza were recorded as monthly total frequencies., Results: Of 2519 IA patients, 88% had confirmed rheumatoid arthritis (RA). Significantly, more IA onsets occurred in winter compared with other seasons (P = 0.03); although IA onset was more frequent in January, the difference between months was not statistically significant. Compared to months with the lowest influenza rates, months with the highest influenza rates had a statistically significant, but trivial, increase of 0.003% in the incidence of IA (incidence rate ratio (95% confidence interval): 1.00003 (1.00005; 1.000053), P = 0.02)., Conclusion: Although IA symptom onset occurs more frequently in winter, we found that flu outbreaks were not associated with a meaningful increase in IA symptom onset in a large, well-characterized cohort of Canadian adults over 6 years., (© 2019 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Purpose: The effectiveness of selective laser trabeculoplasty (SLT) was compared with argon laser trabeculoplasty (ALT) in a randomized clinical trial for patients with medically uncontrolled open-angle glaucoma who have previously received 360° SLT., Design: An active equivalence parallel armed randomized control trial., Participants: Patients with open-angle glaucoma including pigmentary dispersion syndrome and pseudoexfoliation syndrome were enrolled into the study from 7 different sites across Canada., Methods: One setting of 180° of either SLT or ALT was assigned randomly and applied to each participant., Main Outcome Measures: The change in intraocular pressure (IOP) from baseline to 12 months was compared between the 2 groups., Results: A total of 132 patients were recruited, 2 of which dropped out early in the study, leaving 130 patients who completed the study as per protocol. For those, the study's primary outcome was calculated. The IOP change at 1 year in comparison to baseline for SLT vs. ALT was found to be different by 0.33 mmHg between the 2 groups (3.16 for SLT and 2.83 for ALT) and was not statistically significant (P = 0.71) Further analysis, though, showed that SLT had a significantly lower IOP reduction at early time points: 1 week and 1 month, but this effect was lost by 3 months. Corresponding to this finding was the strong trend for ALT to fail more quickly than SLT. Although repeatable, the first repeat SLT reduced IOP to only about half compared with initial SLT treatment., Conclusions: The comparison at 12 months following the laser therapy showed that both modalities lowered the IOP with approximately 3 mmHg, yet essentially all of the time-to-failure analyses favored SLT over ALT. The repeat SLT effect was found to be half of the initial treatment., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are an independent, and possibly causal, risk factor for atherothrombotic diseases including coronary heart disease. The principal evidence base for this comes from large population studies focusing on first atherothrombotic events. However, inconsistent findings have been reported from studies investigating the impact of elevated Lp(a) on atherothrombotic events in subjects with preexisting cardiovascular disease. This question is very important because the secondary prevention population is recommended for Lp(a) screening by some guidelines and could be an important target group for Lp(a)-lowering therapies that are currently on the horizon. In this review, we survey the secondary prevention literature as it relates to Lp(a) and identify some possible confounding factors that may underlie the inconsistent findings, such as index event bias., (Copyright © 2018. Published by Elsevier Inc.)

By their interaction with IgG immune complexes, FcγR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcγR-knockout mice, it has been concluded that FcγRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcγRs (FcγRI/II/III/IV -/- mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcγRIIb-deficient mice, FcγRI/II/III/IV -/- mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcγRs in the modulation of the adaptive immune response in vivo. We conclude that FcγRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Purpose: To investigate whether duration of untreated psychosis (DUP) and duration of untreated illness (DUI) are associated with measures of both subjective and objective recovery 10 years after a first episode of psychosis., Methods: A cohort of 65 clients from an early psychosis intervention program completed a battery of outcome measures 10 years following initial treatment for first-episode psychosis (FEP). The outcomes of interest were self-perceived recovery scores (Maryland Assessment of Recovery in People with Serious Mental Illness Scale) and occupational activity, defined as engagement in work and/or school on a full/part-time basis. Multiple linear and logistic regression analyses were used to estimate the associations between DUP and DUI with each measure of recovery, adjusting for potential confounding factors., Results: We did not find a statistically significant association between DUP and either occupational activity (OR = 1.26, 95% CI 0.81-1.95) or self-perceived recovery score (β = - 0.73, 95% CI - 2.42 to 0.97). However, we found a significant negative association between DUI and self-perceived recovery score (β = - 0.52, 95% CI - 0.87 to - 0.16)., Conclusions: Our findings suggest that DUI may have a stronger influence than DUP on recovery from FEP at 10-year follow-up. This suggests the potential value in targeted interventions for people with a long DUI to increase the likelihood of achieving recovery after the first episode of psychosis.

Cluster randomized trials (CRTs) involve the random assignment of intact social units rather than independent subjects to intervention groups. Time-to-event outcomes often are endpoints in CRTs. Analyses of such data need to account for the correlation among cluster members. The intracluster correlation coefficient (ICC) is used to assess the similarity among binary and continuous outcomes that belong to the same cluster. However, estimating the ICC in CRTs with time-to-event outcomes is a challenge because of the presence of censored observations. The literature suggests that the ICC may be estimated using either censoring indicators or observed event times. A simulation study explores the effect of administrative censoring on estimating the ICC. Results show that ICC estimators derived from censoring indicators or observed event times are negatively biased. Analytic work further supports these results. Observed event times are preferred to estimate the ICC under minimum frequency of administrative censoring. To our knowledge, the existing literature provides no practical guidance on the estimation of ICC when substantial amount of administrative censoring is present. The results from this study corroborate the need for further methodological research on estimating the ICC for correlated time-to-event outcomes. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Neurocutaneous syndromes (or phakomatoses) are a diverse group of congenital disorders that encompass abnormalities of neuroectodermal and, sometimes, mesodermal development, hence commonly involving the skin, eye, and central nervous system. These are often inherited conditions and typically present in early childhood or adolescence. Some of the abnormalities and clinical symptoms may, however, be progressive, and there is an increased risk of neoplastic formation in many of the syndromes. As a group, neurocutaneous syndromes are characterized by distinctive cutaneous stigmata and neurologic symptomology, the latter often representing the most devastating and debilitating features of these diseases. Many of these syndromes are markedly heterogeneous in nature as they affect many organ systems. Given the incurable nature of these conditions and the broad spectrum of pathologies they comprise, treatments vary on a case-by-case basis and tend to be palliative rather than curative. With the advances in molecular genetics, however, greater understanding of biologic functions of the gene products and the correlative phenotypic expression is being attained, and this knowledge may guide future therapeutic developments. This chapter focuses on the cutaneous and neurologic pathology with emphasis on neuroimaging of selective neurocutaneous syndromes, including tuberous sclerosis, Sturge-Weber syndrome, Klippel-Trenaunay syndrome, ataxia-telangiectasia, and incontinentia pigmenti., (© 2016 Elsevier B.V. All rights reserved.)

Background: Childhood anemia is highly prevalent worldwide. Improving the hemoglobin level of preschool age children could yield substantial benefits in cognitive and psychosocial development and overall health. While evidence-based recommendations for reducing childhood anemia in high anemia prevalence countries are available, there is no experimental evidence of community centered education and counseling programs, as a route to improved acceptance of iron supplements, demonstrating beneficial effects on anemia outcomes. We report on the evaluation protocol of a complex educational intervention led by the community lay health worker (LHW) and delivered to mothers of 12-59-month-old anemic children living in and visiting village day care centers in a large district of southern India., Methods and Design: The study is designed as a cluster randomized controlled trial. The intervention is based on the social cognitive theory and aims to promote among mothers, anemia awareness, dietary modifications to increase iron intake in the child, and recognition of the need for enhanced adherence to supplemental iron in the anemic child. From 270 eligible villages in the study area, a sample of 60 villages will be randomized to intervention [n = 30] or to treatment as usual [n = 30] of the study. LHWs in the intervention arm will be trained to administer the following intervention components to mothers of anemic children: 1] monthly distribution of Iron and folic acid (IFA) supplements to mothers of anemic children, and 2] five monthly counseling sessions of mothers of anemic children covering: a] anemia awareness education b] IFA adherence counseling and assessment, c] dietary modification to improve iron intake, and d] hygiene and sanitation. LHWs in the control arm will distribute IFA to mothers of anemic children as in the intervention arm but will not provide monthly education and counseling support. The primary outcome is the difference between the two experimental groups in anemia cure rates of children found to be anemic at baseline. Secondary outcomes, assessed as differences between all participants in both experimental groups, are: change in mothers' knowledge regarding anemia; 24 hour dietary iron intake; net improvement in individual hemoglobin values; serum ferritin; and the difference in overall cluster level childhood anemia prevalence. All outcomes will be measured 6 months after the start of the intervention. Multilevel linear and logistic regression models will be used to analyze differences between intervention and control groups in outcome variables., Discussion: This trial is designed to evaluate the effectiveness of an intervention intended to improve anemia cure rates in anemic children living in villages of Chamarajnagar, Karnataka a large district in south India. The extensive study of secondary endpoints will be used to identify possible weak points in the compliance to intervention delivery and uptake. This evaluation is one of the few large randomized trials evaluating the impact of an education and counseling intervention to reduce childhood anemia prevalence., Trial Registration: This trial was registered with ISRCTN.com (identifier: ISRCTN68413407) on 17 September 2013.

Background: Flail chest injuries are associated with high mortality and morbidity. Despite evidence that operative repair of flail chest is beneficial, it is rarely done. We sought to create a simple risk score using available preoperative covariates to calculate individual risk of mortality in flail chest., Methods: A logistic regression model was trained on Ontario Trauma Registry data to generate a mortality risk score. The final model was validated for calibration and discrimination and corrected for optimism., Results: The model uses five risk factors that are readily obtained during the initial assessment of the trauma patient: age, Glasgow Coma Score, ventilation, cardiopulmonary resuscitation, and number of comorbidities. It was determined that less than 6 points is consistent with 1% observed mortality, 6 to 10 points predicts 5% mortality, 11 to 15 points predicts 22% mortality, and 16 or more points predicts 46% mortality., Conclusions: We have developed a simple model that can be easily applied at bedside to predict mortality in patients with flail chest by accessing a spreadsheet program in an application or other handheld computer device. This model has the potential to be a useful tool for surgeons considering operative repair of flail chest., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Evaluate the ability of the American and British Geriatrics Society fall prevention guideline's screening algorithm to identify and stratify future fall risk in community-dwelling older adults., Methods: Prospective cohort of community-dwelling older adults (n = 117) aged 65 to 90 years. Fall history, balance, and gait measured during a comprehensive geriatric assessment at baseline. Falls data were collected monthly for 1 year. The outcomes of any fall and any injurious fall were evaluated., Results: The algorithm stratified participants into 4 hierarchal risk categories. Fall risk was 33% and 68% for the "no intervention" and "comprehensive fall evaluation required" groups respectively. The relative risk estimate for falling comparing participants in the 2 intervention groups was 2.08 (95% CI 1.42-3.05) for any fall and 2.60 (95% Cl 1.53-4.42) for any injurious fall. Prognostic accuracy values were: sensitivity of 0.50 (95% Cl 0.36-0.64) and specificity of 0.82 (95% CI 0.70-0.90) for any fall; and sensitivity of 0.56 (95% CI 0.38-0.72) and specificity of 0.78 (95% Cl 0.67-0.86) for any injurious fall., Conclusions: The algorithm was able to identify and stratify fall risk for each fall outcome, though the values of prognostic accuracy demonstrate moderate clinical utility. The recommendations of fall evaluation for individuals in the highest risk groups appear supported though the recommendation of no intervention in the lowest risk groups may not address their needs for fall prevention interventions. Further evaluation of the algorithm is recommended to refine the identification of fall risk in community-dwelling older adults.

Purpose: To identify modifiable risk factors associated with the transition from non-faller to faller in community-dwelling older adults., Method: A prospective study design was used. Adults aged 60 to 90 years (n=90, mean age=79.7 years, 63% male) who did not report falling in the past year were included. A comprehensive geriatric assessment was performed at study baseline, and daily falls data were collected monthly for 1 year. Multivariable regression using a modified Poisson model on fall status (yes/no) and a Cox proportional hazards model for time to first fall were used to identify risk factors., Results: Twenty-four people (27%) fell. Modifiable risk factors were present in 67% of study participants, and fall risk increased as the number of risk factors increased. The most common activities performed prior to falling were walking and using stairs. Fall risk doubled ([relative risk=2.00; 95%CI: 1.13-3.56) per unit increase in the number of risk factors (lower-extremity weakness, balance impairment, and ≥4 prescription medications)., Conclusions: Among older adults who were self-reported non-fallers, falls were a common outcome, and modifiable risk factors were present in the majority of the sample. The absence of a fall history does not rule out the need to screen for other risk factors for falls. Functional lower-extremity weakness, balance impairment as measured by the Berg Balance Scale (score <50), and number of risk factors were independent predictors for the transition in status from non-faller to faller. Further research is required to define effective interventions to prevent first falls.

Objectives: To evaluate and summarize the evidence linking balance impairment as a risk factor for falls in community-dwelling older adults., Study Design and Setting: Systematic review and meta-analysis. English language articles in MEDLINE, EMBASE, CINAHL (1988-2009), under keywords of accidental falls, aged, risk factors, and hip, radius, ulna, and humerus fractures; and bibliographies of retrieved articles. Community-dwelling older adults in a prospective study, at least 1-year duration, age more than 60 years, and samples not specific to a single disease-defined population were included. Sample size, inclusion/exclusion criteria, demographics, clinical balance measurement scale, type of fall outcome, method of fall ascertainment, length of follow-up, and odds ratio (OR) or risk ratio (RR) were extracted. Studies must have reported adjustment for confounders. Random effects meta-analysis to generate summary risk estimate was used. A priori evaluation of sources of heterogeneity was performed., Results: Twenty-three studies met the selection criteria. A single summary measure could not be calculated because of the nonequivalence of the OR and RR, producing an overall fall risk of RR of 1.42 (1.08, 1.85) and OR of 1.98 (1.60, 2.46)., Conclusions: Balance impairment imparts a moderate increase on fall risk in community-dwelling older adults. The type of fall outcome, the length of follow-up, and the balance measurement tool impact the magnitude of the association. Specific balance measurement scales were identified with associations for an increased fall risk, but further research is required to refine recommendations for their use in clinical practice., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Screening should have simple and easy-to-administer methods that identify impairments associated with future fall risk, but there is a lack of literature supporting validation for their use., Objective: The aim of this study was to evaluate the independent contribution of balance assessment on future fall risk, using 5 methods to quantify balance impairment, for the outcomes "any fall" and "any injurious fall" in community-dwelling older adults who are higher functioning., Design: This was a prospective cohort study., Methods: A sample of 210 community-dwelling older adults (70% male, 30% female; mean age=79.9 years, SD=4.7) received a comprehensive geriatric assessment at baseline, which included the Berg Balance Scale to measure balance. Information on daily falls was collected for 12 months by each participant's monthly submission of a falls log calendar., Results: Seventy-eight people (43%) fell, of whom 54 (30%) sustained an injurious fall and 32 (18%) had recurrent falls (> or =2 falls). Different balance measurement methods identified different numbers of people as impaired. Adjusted relative risk (RR) estimates for an increased risk of any fall were 1.58 (95% confidence interval [CI]=1.06, 2.35) for self-report of balance problems, 1.58 (95% CI=1.03, 2.41) for one-leg stance, and 1.46 (95% CI=1.02, 2.09) for limits of stability. An adjusted RR estimate for an increased risk of an injurious fall of 1.95 (95% CI=1.15, 3.31) was found for self-report of balance problems. Limitations The study was a secondary analysis of data., Conclusions: Not all methods of evaluating balance impairment are associated with falls. The number of people identified as having balance impairment varies with the measurement tool; therefore, the measurement tools are not interchangeable or equivalent in defining an at-risk population. The thresholds established in this study indicate individuals who should receive further comprehensive fall assessment and treatment to prevent falls.

Hypothesis: Physicians seem to learn best from their peers, yet the impact of opinion leaders on physician behavior is unclear. Because colon cancer staging has been identified as being suboptimal in Ontario, Canada, we sought to evaluate the influence of expert and local opinion leaders for colon cancer on optimizing colon cancer lymph node assessment., Design, Setting, Participants: A cluster-randomized trial including all hospitals in Ontario that identified a local opinion leader with intervention between January 5 and June 17, 2004., Intervention: All 42 centers received a standardized lecture about colon cancer lymph node assessment delivered by an expert opinion leader in colon cancer. The 21 intervention hospitals also received academic detailing of a local opinion leader by the expert opinion leader and a toolkit., Main Outcome Measures: Mean number of lymph nodes assessed in patients with stage II colon cancer and the proportion of cases staged with a minimum of 12 lymph nodes before and after a standardized lecture were assessed., Results: Patient demographic and tumor factors were similar in both groups before and after the standardized lecture. Lymph node assessment significantly improved after the standardized lecture at intervention and control sites (P < .001). No additional benefit of academic detailing and toolkit provision in the intervention was demonstrated., Conclusions: In-person provision of information by an expert opinion leader in colon cancer may stimulate performance regarding lymph node assessment for colon cancer. Academic detailing of a local opinion leader did not further improve lymph node assessment.

In cluster randomized trials, intact social units such as schools, worksites or medical practices - rather than individuals themselves - are randomly allocated to intervention and control conditions, while the outcomes of interest are then observed on individuals within each cluster. Such trials are becoming increasingly common in the fields of health promotion and health services research. Attrition is a common occurrence in randomized trials, and a standard approach for dealing with the resulting missing values is imputation. We consider imputation strategies for missing continuous outcomes, focusing on trials with a completely randomized design in which fixed cohorts from each cluster are enrolled prior to random assignment. We compare five different imputation strategies with respect to Type I and Type II error rates of the adjusted two-sample t -test for the intervention effect. Cluster mean imputation is compared with multiple imputation, using either within-cluster data or data pooled across clusters in each intervention group. In the case of pooling across clusters, we distinguish between standard multiple imputation procedures which do not account for intracluster correlation and a specialized procedure which does account for intracluster correlation but is not yet available in standard statistical software packages. A simulation study is used to evaluate the influence of cluster size, number of clusters, degree of intracluster correlation, and variability among cluster follow-up rates. We show that cluster mean imputation yields valid inferences and given its simplicity, may be an attractive option in some large community intervention trials which are subject to individual-level attrition only; however, it may yield less powerful inferences than alternative procedures which pool across clusters especially when the cluster sizes are small and cluster follow-up rates are highly variable. When pooling across clusters, the imputation procedure should generally take intracluster correlation into account to obtain valid inferences; however, as long as the intracluster correlation coefficient is small, we show that standard multiple imputation procedures may yield acceptable type I error rates; moreover, these procedures may yield more powerful inferences than a specialized procedure, especially when the number of available clusters is small. Within-cluster multiple imputation is shown to be the least powerful among the procedures considered., (Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Trials in which intact communities are the units of randomization are increasingly being used to evaluate interventions which are more naturally administered at the community level, or when there is a substantial risk of treatment contamination. In this article we focus on the planning of community intervention trials in which k communities (for example, medical practices, worksites, or villages) are to be randomly allocated to each of an intervention and a control group, and fixed cohorts of m individuals enrolled in each community prior to randomization. Formulas to determine k or m may be obtained by adjusting standard sample size formulas to account for the intracluster correlation coefficient rho. In the presence of individual-level attrition however, observed cohort sizes are likely to vary. We show that conventional approaches of accounting for potential attrition, such as dividing standard sample size formulas by the anticipated follow-up rate pi or using the average anticipated cohort size m pi, may, respectively, overestimate or underestimate the required sample size when cluster follow-up rates are highly variable, and m or rho are large. We present new sample size estimation formulas for the comparison of two means or two proportions, which appropriately account for variation among cluster follow-up rates. These formulas are derived by specifying a model for the binary missingness indicators under the population-averaged approach, assuming an exchangeable intracluster correlation coefficient, denoted by tau. To aid in the planning of future trials, we recommend that estimates for tau be reported in published community intervention trials., ((c) 2006 John Wiley & Sons, Ltd.)

Matched-pair cluster randomization trials are frequently adopted as the design of choice for evaluating an intervention offered at the community level. However, previous research has demonstrated that a strategy of breaking the matches and performing an unmatched analysis may be more efficient than performing a matched analysis on the resulting data, particularly when the total number of communities is small and the matching is judged as relatively ineffective. The research concerning this question has naturally focused on testing the effect of intervention. However, a secondary objective of many community intervention trials is to investigate the effect of individual-level risk factors on one or more outcome variables. Focusing on the case of a continuous outcome variable, we show that the practice of performing an unmatched analysis on data arising from a matched-pair design can lead to bias in the estimated regression coefficient, and a corresponding test of significance which is overly liberal. However, for large-scale community intervention trials, which typically recruit a relatively small number of large clusters, such an analysis will generally be both valid and efficient. We also consider other approaches to testing the effect of an individual-level risk factor in a matched-pair cluster randomization design, including a generalized linear model approach that preserves the matching, a two-stage cluster-level analysis, and an approach based on generalized estimating equations.

Background: A significant gap has been documented between best practice and the actual practice of surgery. Our group identified that colorectal cancer staging in Ontario was suboptimal and subsequently developed a knowledge translation strategy using the principles of social marketing and the influence of expert and local opinion leaders for colorectal cancer., Methods/design: Opinion leaders were identified using the Hiss methodology. Hospitals in Ontario were cluster-randomized to one of two intervention arms. Both groups were exposed to a formal continuing medical education session given by the expert opinion leader for colorectal cancer. In the treatment group the local Opinion Leader for colorectal cancer was detailed by the expert opinion leader for colorectal cancer and received a toolkit. Forty-two centres agreed to have the expert opinion leader for colorectal cancer come and give a formal continuing medical education session that lasted between 50 minutes and 4 hours. No centres refused the intervention. These sessions were generally well attended by most surgeons, pathologists and other health care professionals at each centre. In addition all but one of the local opinion leaders for colorectal cancer met with the expert opinion leader for colorectal cancer for the academic detailing session that lasted between 15 and 30 minutes., Discussion: We have enacted a unique study that has attempted to induce practice change among surgeons and pathologists using an adapted social marketing model that utilized the influence of both expert and local opinion leaders for colorectal cancer in a large geographic area with diverse practice settings.

We obtain the asymptotic sample variance of the intraclass kappa statistic for multinomial outcome data. A modified Wald type procedure based on this theory is then used for confidence interval construction. The results of a simulation study show that the proposed non-iterative approach performs very well in terms of confidence interval coverage and width for samples as small as 50. The procedure is illustrated with two examples from previously published medical studies.

Objective: This is the first study to evaluate the association between colonic screening and colorectal cancer risk among Canadians., Methods: A case-control study was conducted. Cases were diagnosed with cancer of the colorectum, between 1997 and 2000, aged 20 to 74 years, identified through the population-based Ontario Cancer Registry and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex- and age-matched random sample of the population of Ontario. 971 cases and 1944 controls completed questionnaires (including colorectal screening history and many risk factors). Multivariate logistic regression analysis was used to obtain adjusted odds ratios (OR) estimates., Results: Having had a fecal occult blood screen was associated with reduced colorectal cancer risk (OR=0.76; 95% confidence interval (CI): 0.59, 0.97). Having had a screening sigmoidoscopy was associated with a halving of colorectal cancer risk (OR = 0.52; 95% CI: 0.34, 0.80). Having had a screening colonoscopy did not significantly reduce colorectal cancer risk (OR = 0.69; 95% CI: 0.44, 1.07); however, having had either screening endoscopy was associated with a significant reduction in colorectal cancer risk (OR = 0.62; 95% CI: 0.44, 0.87). Findings differed slightly by anatomic sub-site (proximal and distal colorectum)., Conclusions: We report a reduction in colorectal cancer risk among persons who underwent colorectal cancer screening; in particular, sigmoidoscopy. Findings are of great importance for the prevention of colorectal cancer.

Use of self-reported confidence ratings may be an efficient method for assessing recall bias. In this exploratory application of the method, the authors examined the relation between case-control status and self-reported confidence ratings. In 2002 and 2003, melanoma cases (n = 141) and controls (n = 143) aged 20-44 years residing in Ontario, Canada, estimated the amounts of time they had spent outdoors in summer activities when they were 6-18 years of age and indicated their confidence in the accuracy of each estimate. The generalized estimating equations extension of logistic regression was used to examine dichotomized confidence ratings (more confident vs. less confident) for activities reported for ages 6-11 years and 12-18 years. Types of activity were associated with more confident reporting for both age strata; as the number of stable outdoor activity periods (total number of similar outdoor periods within each activity) reported by respondents increased, confidence decreased. Cumulative time spent outdoors was also associated with more confidence but reached statistical significance only for the age stratum 12-18 years. There was no statistically significant association between case-control status and self-reported confidence for either age stratum (6-11 years: odds ratio = 0.91; 12-18 years: odds ratio = 1.32), which suggests an absence of recall bias for reported time spent outdoors.

Objectives: To compare interval cancer rates, sensitivity and specificity of breast cancer screening between women with moderate or strong family history and women without a family history., Methods: From 1996 to 1997, 115,460 women aged 50 to 69 screened by the Ontario Breast Screening Program, offering eligible women screening with mammography and clinical breast examination, were examined. Women were followed for up to 12 months after their screening examination. Family history definitions were based on the number of affected first degree relatives and their ages at diagnosis. Multivariate analysis was conducted to adjust for potential confounding variables., Results: Interval cancer rates increased across family history groups and were greatest in women with a strong family history. The rate ratio (RR) for interval cancer rate in women with a strong family history compared to women without a family history approached significance (RR=2.28, 95% confidence interval (CI) 0.97-5.34), while for women with a moderate family history it did not (RR=1.37, 95% CI 0.62-3.04). A slightly but not significantly lower sensitivity was observed in women with a strong family history compared to women without a family history. There was little variation in specificity across family history groups., Conclusions: Screening was able to detect a large proportion of invasive breast cancers in women with a family history, indicating their potential to benefit from regular breast cancer screening. However, due to increased interval cancer rates, screening with one-year intervals may be important even in an older population of women with a family history.

Background: Cervical cancer remains a significant yet preventable disease despite the widespread availability of Pap test screening, which detects cervical cancer and its precursor lesions. The aims of this study were to: i) estimate and compare age- and hysterectomy-adjusted Pap test rates across the 37 Ontario public health units (PHUs), and ii) explore the association between several factors and Pap test rates (at the ecological level)., Methods: Cytobase, an Ontario Pap test registry, captures more than 80% of all Pap tests in Ontario. Cytobase was used to determine Pap test rates adjusted for age, hysterectomy and Cytobase coverage for the year 2001. Multiple linear regression analyses were used to evaluate the relationship between Pap test rates and various factors at an ecological level,, Results: Age-, hysterectomy- and Cytobase-adjusted one-year Pap rates ranged from 11.6% to 73.9% among PHUs. The overall rate for Ontario was 40.7%. Multivariate analyses indicated that the presence of a teaching hospital was associated with higher Pap test rates., Conclusion: One-year Pap test rates varied greatly across the 37 public health units in Ontario. Pap test rates determined using Cytobase were lower than self-reported rates obtained from the Canadian Community Health Survey, possibly due to "over-reporting". In general, women were not screened as frequently as recommended by the Ontario Cervical Screening Program. A positive association was observed between Pap test rates and the presence of a teaching hospital. Data quality issues limit the ability to monitor cervical screening. A provincial registry would address these issues.

Background: Cluster randomization trials in which intact social units are randomly assigned to different intervention groups have become very popular in recent years, particularly for the evaluation of innovations in the delivery of health care. An extensive literature dealing with the associated methodological challenges has also appeared. Although the monitoring of such trials using formal stopping rules is clearly indicated when the outcomes are irreversible and individual-level data are available sequentially, simple and reliable statistical methods that may be used for this purpose are currently not available., Purpose: To investigate the validity of standard group sequential methods when applied to cluster randomization trials having binary outcomes., Methods: The large sample distributions for each of five test statistics computed from sequentially accumulated data are derived. A simulation study is performed to evaluate the finite sample properties of these statistics when applied to the interim analysis of cluster randomization trials. Data from the World Health Organization antenatal care trial are used to illustrate the methods., Results: Each of the joint distributions is shown to be characterized by a covariance structure that asymptotically satisfies an independent increments structure, a foundation that simplifies group sequential methods. The simulation study reveals that four of the five test statistics evaluated provide satisfactory performance with as few as 10 clusters allocated to each of two interventions., Limitations: The applicability of our results to effect estimation following a group sequential cluster randomization trial is not investigated, although a theoretical foundation which may be used for this purpose is presented., Conclusions: Standard group sequential methods can be applied to cluster randomization trials when interim analyses are warranted.

Split-cluster designs are frequently used in the health sciences when naturally occurring clusters such as multiple sites or organs in the same subject are assigned to different treatments. However, statistical methods for the analysis of binary data arising from such designs are not well developed. The purpose of this article is to propose and evaluate a new procedure for testing the equality of event rates in a design dividing each of k clusters into two segments having multiple sites (e.g., teeth, lesions). The test statistic proposed is a generalization of a previously published procedure based on adjusting the standard Pearson chi-square statistic, but can also be derived as a score test using the approach of generalized estimating equations.

Cancer risk programs rely on accurately reported family history information. This study compares the accuracy with which cancer sites and ages at diagnosis are reported by Li-Fraumeni syndrome (LFS) and hereditary breast-ovarian cancer syndrome (HBOCS) families undergoing genetic testing. We analyzed the accuracy of 191 cancer diagnoses among first-degree (FDRs) and second-degree (SDRs) relatives reported by 32 LFS and 52 HBOCS participants in genetic testing programs. Cancer diagnoses of relatives were more accurately reported in the HBOCS cohort (78%) than in the LFS cohort (52%). Almost all breast cancer diagnoses were accurately reported, whereas 74% of ovarian cancer diagnoses and only 55% of other LFS-related cancers were accurately reported. Age at diagnosis was accurate within 5 years for 60% of LFS relatives and 53% of HBOCS relatives. Factors correlating with accurate reporting of cancer history included: being member of BRCA1 family, higher education level, female historian, degree of closeness to affected relative, and having fewer than 5 affected FDRs and SDRs. Relying on verbal histories would not have altered eligibility for genetic testing among HBOCS historians, but fewer than half of LFS historians provided information that would have led to TP53 testing. Our data suggest that it may not be necessary to confirm breast cancer diagnoses routinely; however, documentation of other cancer types remains important for appropriate risk assessment and follow-up.

Randomized trials are often designed to assess an intervention's ability to change patient knowledge, behaviour or health. The study outcome will then need to be measured at least twice for each subject--prior to random assignment and following implementation of the intervention. In this paper we consider methods for modelling change when data are obtained from cluster randomization trials where the unit of allocation is a family, school or community. Attention focuses on mixed effects linear regression extensions of (i) two-sample t-tests and (ii) analysis of covariance, in both cases accounting for dependencies among cluster members. Algebraic expressions for tests of the intervention effect are derived for the special case where there are a fixed number of subjects per cluster while simulation studies are used to compare the power of these procedures in the more realistic case where there is variability in cluster size. A key conclusion is that there can be considerable gains in power when allowing for different individual-level and cluster-level associations between the baseline and follow-up assessments. The discussion is illustrated using data from a school-based smoking prevention trial.

It is now well known that standard statistical procedures become invalidated when applied to cluster randomized trials in which the unit of inference is the individual. A resulting consequence is that researchers conducting such trials are faced with a multitude of design choices, including selection of the primary unit of inference, the degree to which clusters should be matched or stratified by prognostic factors at baseline, and decisions related to cluster subsampling. Moreover, application of ethical principles developed for individually randomized trials may also require modification. We discuss several topics related to these issues, with emphasis on the choices that must be made in the planning stages of a trial and on some potential pitfalls to be avoided.

BACKGROUND: Vaccines have virtually eliminated many diseases, but public concerns about their safety could undermine future public health initiatives. OBJECTIVE: To determine Canadians' attitudes and knowledge about vaccines, particularly in view of increasing public concern about bioterrorism and the possible need for emergency immunizations after weaponized anthrax incidents and the events of September 11, 2001. METHOD: A 20-question survey based on well-researched dimensions of vaccine responsiveness was telephone-administered to a random sample of N = 1330 adult Canadians in January, 2002. RESULTS: 1057 (79.5%) completed the survey. Respondents perceived vaccines to be highly effective and demonstrated considerable support for further vaccine research. However, results also indicate a lack of knowledge about vaccines and uncertainty regarding the safety. CONCLUSIONS: Support for vaccines is broad but shallow. While Canadians hold generally positive attitudes about vaccines, support could be undermined by widely publicized adverse events. Better public education is required to maintain support for future public health initiatives.

Meta-analyses involving the synthesis of evidence from cluster randomization trials are being increasingly reported. These analyses raise challenging methodologic issues beyond those raised by meta-analyses which include only individually randomized trials. In this paper we review and comment on a selected number of these issues, including problems of study heterogeneity, difficulties in estimating design effects from individual trials and the choice of statistical methods., (Copyright 2002 John Wiley & Sons, Ltd.)

Purpose: The Human Genome Project continues to produce an increasing number of genetic susceptibility tests. Some of these genetic tests target social or ethnic groups who are at increased risk of developing a disease. The Ashkenazi Jewish community is one ethnic group that is an ongoing subject of genetic investigation. We assessed the attitudes of a population-based sample of Ashkenazi Jewish women toward breast-ovarian cancer susceptibility testing (BRCA 1/2). In particular, we assessed concerns about group discrimination, perceptions of the advantages and disadvantages of testing, and the relationship between concerns about discrimination and the potential benefits of genetic testing., Methods: A telephone survey of a population-based sample of 200 Jewish women., Results: A minority of women (17%) in this study expressed concern or discomfort with Jews being offered testing. Most women believed there were scientific reasons for testing Jews (71%), and only 5% of women felt that research that focused on Jews was bad for Jews as a group. Increased concern about genetic discrimination was associated with women who were highly educated (odds ratio 2.68). Forty percent of women surveyed were interested in testing, 40% were not interested, and 20% were uncertain about whether they would obtain testing. Increased interest in genetic testing was associated with a desire to obtain information about children's risk of disease and valuing information for its own sake., Conclusions: The majority of a population-based sample of Jewish women did not express concerns about group discrimination resulting from genetic testing. Women who are highly educated are more concerned about genetic discrimination. There is significant variation among Jewish women's interest in breast cancer susceptibility testing.

Cluster randomization trials in which families are the unit of allocation are commonly adopted for the evaluation of disease prevention interventions. Sample size estimation for cluster randomization trials depends on parameters that quantify the variability within and between clusters and the variability in cluster size. Accurate advance estimates of these nuisance parameters may be difficult to obtain and misspecification may lead to an underpowered study. Since families are typically recruited over time, we propose using a portion of the data to estimate the nuisance parameters and to re-estimate sample size based on the estimates. This extends the standard internal pilot study methods to the setting of cluster randomization trials. The effect of this design on the power, significance level and sample size is analysed via simulation and is shown to provide a flexible and practical approach to cluster randomization trials.

Objective: The impact of worksite intervention studies is maximized when reach and enrollment are high and attrition is low. Differences in reach, enrollment, and retention were investigated by comparing 2 different employee recruitment methods for a home-based cancer-prevention intervention study., Methods: Twenty-two worksites (N = 10,014 employees) chose either active or passive methods to recruit employees into a home-based intervention study. Reach (e.g., number of employees who gave permission to be called at home), Enrollment (e.g., number of employees who joined the home intervention study), and Attrition (e.g., number who did not complete the 12- and 24-month follow-ups) were determined. Analysis at the cluster level assessed differences between worksites that selected active (n = 12) versus passive (n = 10) recruitment methods on key outcomes of interest. Employees recruited by passive methods had significantly higher reach (74.5% vs. 24.4% for active) but significantly lower enrollment (41% vs. 78%) and retention (54% vs. 70%) rates (all ps < .0001). Passive methods also successfully enrolled a more diverse, high-risk employee sample. Passive (vs. active) recruitment methods hold advantages for increased reach and the ability to retain a more representative employee sample. Implications of these results for the design of future worksite studies that involve multilevel recruitment methods are discussed.

We propose a new procedure for constructing inferences about a measure of interobserver agreement in studies involving a binary outcome and multiple raters. The proposed procedure, based on a chi-square goodness-of-fit test as applied to the correlated binomial model (Bahadur, 1961, in Studies in Item Analysis and Prediction, 158-176), is an extension of the goodness-of-fit procedure developed by Donner and Eliasziw (1992, Statistics in Medicine 11, 1511-1519) for the case of two raters. The new procedure is shown to provide confidence-interval coverage levels that are close to nominal over a wide range of parameter combinations. The procedure also provides a sample-size formula that may be used to determine the required number of subjects and raters for such studies.

Purpose: Mammograms and breast examinations are established methods for early breast cancer detection. Routine mammography screening reduces breast cancer mortality among women ages > or = 50 years, but additional screening methods are needed. We and others have found high levels of carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) in nipple aspirate fluids (NAFs), but the usefulness for these bio-markers for early breast cancer detection is unknown., Patients and Methods: NAFs from one or both breasts of 388 women were analyzed for CEA, PSA, and albumin levels. The study included 44 women with newly diagnosed invasive breast cancers, 67 women with proliferative breast lesions (ductal and lobular carcinoma in situ and atypical ductal hyperplasia), and 277 controls without these breast lesions. Analyses were conducted using the log(10)-transformed CEA and PSA levels to normalize the distributions of these tumor markers., Results: Nipple fluid CEAs are significantly higher for cancerous breasts than tumor-free breasts (median 1,830 and 1,400 ng/mL, respectively; P <.01). However, at 90% specificity of the assay (CEA = 11,750 ng/mL), the corresponding sensitivity for cancer detection is 32%. CEA levels are not significantly different for breasts with proliferative lesions compared with tumor-free breasts. Nipple fluid PSAs do not differ by tumor status. Analyses of NAF albumin-standardized CEAs and PSAs yield similar results. Nipple fluid CEA and PSA titers are correlated in the affected and unaffected breast of women with unilateral lesions., Conclusion: Nipple fluid CEAs are higher for breasts with untreated invasive cancers, but the test sensitivity is low. Nipple fluid PSA titers do not seem to be useful for breast cancer detection.

Purpose: The cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL) were compared in a group of patients who received dexamethasone during the intensification and maintenance phases of therapy with those in a historical control group for whom antileukemia therapy was similar, except that the corticosteroid component of therapy was prednisone., Methods: Patients treated for ALL on Dana-Farber Cancer Institute protocols 87-01 (n = 44) and 91-01 (n = 23) were evaluated by standard cognitive and achievement tests. Corticosteroid therapy was delivered in 5-day pulses given every 3 weeks during intensification and continuation phases of therapy for a total of 2 years., Results: Children treated on protocol 87-01 received prednisone at a dose of 40 mg/m2/d (standard risk, SR) or 120 mg/ m2/d (high risk, HR); those treated on protocol 91-01 received dexamethasone at a dose of 6 mg/m2 per day (SR) or 18 mg/m2 per day (HR). Children treated on protocol 91-01 performed less well on cognitive testing. Subsample analysis indicated that cranial radiation therapy and methotrexate dose did not account for differences in cognitive outcomes., Conclusions: The findings of this preliminary study are consistent with the hypothesis that dexamethasone therapy can increase risk for neurocognitive late effects in children treated for ALL and indicate that further investigation of this question is warranted.

Considerable research attention has been given to the impact of genetic testing on psychological outcomes. Participation in genetic testing also may impact on health behaviors that increase the risk of cancer and other chronic diseases. The purpose of this study is to describe behavioral cancer risk factors of women who requested genetic testing for breast and ovarian cancer susceptibility (BRCA1, BRCA2). Before participation in a genetic testing program, 119 women completed a series of questionnaires designed to assess their health behaviors, perception of risk, and depressive symptomatology. Eight percent of participants were current smokers, 27% did not engage in at least moderate exercise, 46% did not regularly protect themselves from the sun, 39% did not consume at least five servings of fruits and vegetables per day, and 9% drank at least one alcoholic beverage per day. Poisson regression analysis revealed that age was the only predictor of behavioral risk profiles, with older women having fewer cancer risk behaviors. These patients who presented for genetic testing generally had better health behaviors than the general population. However, given their possible high-risk status, these patients should consider further improving their preventable cancer risk factors and, in particular, their diet, sun protection, and physical activity levels. Inclusion of behavioral risk factor counseling in the context of the genetic testing process may be an important opportunity to reach this at-risk population.

Purpose: Few studies have formally evaluated the relationship between costs, baseline patient characteristics, and major complications of stem-cell transplantation. We sought (1) to determine whether obtaining baseline information enabled identification of patients whose treatments would be the most costly and (2) to estimate inpatient costs for managing specific transplantation complications., Patients and Methods: We collected inpatient costs and clinical information for 236 consecutive patients undergoing transplantation at a single institution between July 1, 1994, and February 20, 1997. Multivariable linear regression was used to evaluate the associations between baseline patient characteristics and costs of hospitalization for initial transplantation and between clinical events and such costs., Results: The median initial inpatient cost in 1997 dollars was $55,500 for autologous transplantation (range, $28,200 to $148,200) and $105,300 for allogeneic transplantation (range, $32,500 to $338,000). When only baseline variables were considered, use of a mismatched allogeneic donor and year of transplantation were significant predictors of costs. No characteristics predicted which patients would incur the highest 10% of costs. When clinical events were considered, infection and in-hospital death were associated with higher costs in autologous transplant recipients ($18,400 and $20,500, respectively), whereas infection, veno-occlusive disease, acute graft-versus-host disease, and death were predicted to add between $15,300 and $28,100 each to allogeneic transplantation costs., Conclusion: We were not able to identify before transplantation the patients whose treatments would be the most costly. However, the association between clinical complications and higher costs suggests that prevention may have significant economic benefits. Interventions that decrease these complications may have favorable cost-benefit ratios even if they do not affect overall survival.

Summary: : We evaluated the use of utility measurements to assess the quality of life of patients with Crohn's disease. Utility scores were obtained using the Time Trade-Off (TTO), Standard Gamble, and Visual Analog Scale (VAS) methods in 180 consecutive patients with Crohn's disease. The mean utility scores of patients with a spectrum of disease severity were compared with other measures of disease activity to assess the operating properties of these instruments. All methods of utility estimation yielded lower mean scores in patients with more severe disease. (Remission versus chronically active, therapy resistant disease: TTO 0.96 versus 0.88; Standard Gamble 0.88 versus 0.74; VAS 0.84 versus 0.61). TTO scores were consistently higher than those derived by the other methods (p = 0.001). The utility scores were reliable in patients who were stable (intraclass correlation coefficient 0.55-0.84), but were less responsive than the Crohn's Disease Activity Index (responsiveness ratio 0.97-1.3 versus 2.10) to changes in disease severity. Patients with active Crohn's disease have decreased quality of life as measured by utility scores. Although utilities are valid and reliable quality of life assessments, they are less responsive than other measures of outcome used for clinical trials.

Procedures are compared for testing the homogeneity of k > or = 2 independent kappa statistics in the case of two raters and a dichotomous outcome. One of the procedures is based on the estimated large sample variance derived under a model frequently adopted for inferences concerning interobserver agreement. The other is based on a goodness-of-fit approach to this model. The results of a Monte Carlo simulation show that the two approaches have similar properties if the number of subjects in each sample is large (> 100), and the prevalence of the underlying trait of interest is not extreme, while the goodness-of-fit approach is recommended for comparisons involving smaller numbers of subjects or in which the prevalence of the underlying trait is small (< 0.3).

Field trials in tropical medicine are often designed so that intact social units (e.g., families, schools, communities) rather than independent individuals are randomized to an intervention group. Reasons are diverse, but include administrative convenience, a desire to reduce the effect of treatment contamination, and the need to avoid ethical issues that might otherwise arise. Dependencies among cluster members typical of such designs must be considered when determining sample size and analysing the resulting data. Failure to do so can result in false conclusions that the treatment is effective. The purpose of this paper is to compare different methods which can be used to construct tests of the effect of treatment when outcomes are binary (e.g., infected/uninfected). The discussion will be illustrated using data from a trial which randomly assigned families to either a control group or a screening and treatment programme for imported intestinal parasites.

Statistical methodology is presented for the estimation of twin similarity with respect to a dichotomous trait. The methodology focuses on the intraclass correlation as the parameter of interest and is analogous to methodology commonly applied to continuous outcome data. For inference problems involving a single sample, confidence interval construction and significance testing are discussed. For two sample problems, test procedures are provided that are an alternative to an approach recently presented by Ramakrishnan et al. [(1992) Genet Epidemiol 9:273-287 (1)]. Two examples based on published data sets are given to illustrate the proposed techniques.