The development of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE): a novel strategy for measuring the clinical utility of genetic testing.

PURPOSE: Clinical utility describes a genetic test's value to patients, families, health-care providers, systems, or society. This study aims to define clinical utility from the perspective of clinicians and develop a novel outcome measure that operationalizes this concept. METHODS: Item selection for the Clinician-reported Genetic testing Utility InDEx (C-GUIDE) was informed by a scoping review of the literature. Item reduction was guided by qualitative and quantitative feedback from semistructured interviews and a cross-sectional survey of genetics and nongenetics specialists. Final item selection, index scoring, and structure were guided by feedback from an expert panel of genetics professionals. RESULTS: A review of 194 publications informed the selection of a preliminary set of 25 items. Feedback from 35 semistructured interviews, 113 surveys, and 11 expert panelists informed the content and wording of C-GUIDE's final set of 18 items that reflect on the utility of testing related to diagnosis, management, and familial/psychosocial impact. C-GUIDE achieves content and face validity for use in a range of diagnostic genetic testing settings. CONCLUSION: Work to establish reliability and construct validity is underway. C-GUIDE will be useful in comparative studies to generate policy-relevant evidence pertaining to the clinical utility of genetic testing across a range of settings.

Vitamin D and progression of carotid intima-media thickness in HIV-positive Canadians.

OBJECTIVES: Based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), we hypothesized that in Canadian HIV-positive adults, low 25-hydroxyvitamin D (25(OH)D) concentration would be associated with increased subclinical vascular disease progression. METHODS: We prospectively studied the relationship between baseline 25(OH)D and subsequent progression of carotid intima-media thickness (CIMT) between 2002 and 2011, in the Canadian HIV Vascular Study using stored blood specimens. RESULTS: Of the 128 participants, 89.1% were men, the mean age (standard deviation [SD]) was 46.5 (8.2) years, 93.8% were white, and 36.7% were current smokers. Mean (SD) annual CIMT follow-up was 5.9 (1.8) years (maximum 8.5 years), providing approximately 750 patient-years of follow-up. Mean (SD) CIMT progression was 0.027 (0.030) mm/year. Mean (SD) 25(OH)D was 95.0 (46.9) nmol/L. Only 13.3% of participants were vitamin D deficient (25(OH)D < 50 nmol/L), whereas 61.7% had a 25(OH)D exceeding the sufficiency threshold (75 nmol/L). Vitamin D quartiles were inversely associated with body mass index (BMI) (P = 0.034), total cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P = 0.001) and parathyroid hormone concentration (P = 0.003), but not efavirenz exposure (P = 0.141). In linear regression analyses, baseline 25(OH)D as a continuous variable was inversely associated with CIMT progression in univariable (P < 0.001) and multivariable (P < 0.001) models. CONCLUSIONS: Baseline 25(OH)D was associated with CIMT progression in this relatively vitamin D replete, predominately white and male, Canadian HIV-positive population. Future research needs to establish causality as this may warrant more targeted screening or supplementation.

Role of pharmaceutical care for self-administered pulmonary tuberculosis treatment in Thailand.

WHAT IS KNOWN AND OBJECTIVE: With resource constraints in Thailand, directly observed therapy (DOT) for treating tuberculosis (TB) may not be feasible to implement. To improve patients' adherence, hospitals either modify DOT or adopt different approaches: pharmaceutical care or home visit. Our objective was to assess pulmonary TB treatment success rate of pharmaceutical care compared to home visit and modified DOT in Thailand. METHODS: We conducted a retrospective cohort study using data collected in adult pulmonary TB patients starting treatment between October 2010 and September 2013 in three hospitals in Thailand. This study was approved by the Research Ethics Board at each of the participating hospitals. We built a propensity score matching to account for differences in patient baseline characteristics. RESULTS: Analysis included 1398 patients. Before matching, the treatment success rate for patients receiving pharmaceutical care was 94.9%, home visit 93.6% and modified DOT 90.1%. The propensity score-matched cohorts indicated that differences in the treatment success rate were not statistically significant when comparing pharmaceutical care with either home visit (success rate: 92.76% vs 94.74%, risk difference: 1.97%, 95% CI -3.64 to 7.59) or modified DOT (success rate 93.37% for both, risk difference: 0%, 95% CI -5.30 to 5.30). WHAT IS NEW AND CONCLUSION: Pharmaceutical care, home visit and modified DOT are all associated with high success rate for pulmonary TB treatment and exceeded the WHO target, in this retrospective analysis.

Pilot study of once-a-day prophylaxis for youth and young adults with severe haemophilia A.

INTRODUCTION: Standard prophylaxis has been shown to be an effective treatment for severe haemophilia A. According to pharmacokinetic principles, daily factor infusions of smaller doses can maintain similar trough factor VIII (FVIII) levels, and perhaps the same protection as standard prophylaxis. AIM: This multicentre study examined the feasibility of daily prophylaxis for youth and young adults with severe haemophilia A in Montreal and Toronto. METHODS: Bleeding rates, joint status, quality of life and physical activity were monitored for 14 patients during this study. At baseline, subjects continued their regular treatment regimen and switched to daily prophylaxis after 4 months; nine had begun daily prophylaxis before enrolment. Additional visits occurred at 8 and 12 months which included a physical examination, inhibitor testing, HJHS and FISH assessments, the CHO-KLAT/Haemo-QoL-A and PDPAR. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication ver.II and perceived difficulty questions at the end of study. RESULTS AND CONCLUSIONS: There were no significant changes in quality of life except for concerns with the demanding daily infusion schedule. The number of bleeds did not statistically differ from the initial 4 months of the study to the last 8 months. Monthly bleeding rates from the year prior to the study and during the intervention phase were not statistically different. It was also found that daily prophylaxis used 24% less FVIII compared to standard prophylaxis. Taking all of this into account, we have found that providing daily prophylaxis is feasible and that it is feasible to prospectively study daily prophylaxis in youth and young adults.

Timing of low bone mineral density and predictors of bone mineral density trajectory in children on long-term warfarin: a longitudinal study.

UNLABELLED: We studied bone mineral density (BMD) of children exposed to long-term warfarin. BMD Z-scores ≤ -2.0 were estimated to occur in less than one fifth of the patients after 10 years of warfarin exposure, and BMI and growth hormone deficiency predicted BMD changes over time. These predictors can help identify high-risk patients. INTRODUCTION: Children with chronic diseases are at increased risk of developing thrombosis, which may require long-term warfarin therapy. Warfarin could further jeopardize the bone health of a population already at risk for bone fragility. Our objective was to investigate the occurrence and timing of low bone mineral density (BMD) and the predictors that influence BMD trajectory in children receiving warfarin for >1 year. METHODS: We analyzed the results of an institutional protocol that includes dual-energy X-ray absorptiometry, with or without spinal X-rays and laboratory biomarkers, as required. RESULTS: Low BMD (age, sex, race, and height-for-age-Z-score adjusted BMD Z-score ≤ -2.0) was detected in 13 % (9/70) of the patients at some point during their follow-up; these patients were more likely to have complex underlying medical conditions and low body mass index (BMI) percentile. BMD Z-scores remained within normal range in 87 % of children. Survival analysis showed that the estimated 10-year abnormal BMD-free rate for the entire group was 81 % (95 % confidence interval [CI] 69 to 93 %). Trajectory analysis revealed that BMI percentiles at baseline and growth hormone deficiency (GHD) were associated with lower BMD Z-scores at the first assessment, whereas baseline BMI percentile was the only predictor of BMD Z-score over time. CONCLUSIONS: Our findings identified BMI and GHD as risk factors influencing BMD in children exposed to long-term warfarin, creating an opportunity for early detection and intervention in these patients.

Pregnancy complications associated with the co-prevalence of excess maternal weight and depression.

OBJECTIVES: Obesity and depression have become prevalent pregnancy complications, individually associated with adverse perinatal health outcomes. Despite the co-prevalence of these two risk factors, their combined effects on maternal health are yet to be studied. The objective of this study was to examine the combined associations of overweight/obesity and depression with maternal and delivery complications. METHODS: A retrospective cohort study of women with singleton gestations at >20 weeks, in Ontario, Canada (April 2007 to March 2010), was conducted. Our primary outcomes were a composite of maternal complications (for example, gestational hypertension, pre-eclampsia, preterm premature rupture of membranes and so on), and a composite of delivery complications (for example, caesarean delivery, shoulder dystocia, postpartum haemorrhage and so on). RESULTS: The study population consisted of 70 605 women, of whom 50.3% were overweight/obese. Depression was reported in 5.0% of normal-weight women and 6.2% of overweight/obese women. The proportion of women with maternal complications was the highest among the overweight/obese depressed pregnant women (16% of normal-weight non-depressed, 22% of normal-weight depressed, 22% of overweight/obese non-depressed and 29% of overweight/obese depressed, P<0.001), as was the proportion of women with delivery complications (44%, 49%, 50% and 53%, respectively, P<0.001). Overweight/obese depressed pregnant women also experienced the highest odds of the composite of maternal complications and the composite of delivery complications (adjusted odds ratio (OR): 1.55, 95% confidence interval (CI): 1.35-1.77 and OR: 1.27, 95% CI: 1.13-1.42, respectively) after adjustment for potential confounders. CONCLUSIONS: The combined associations of excess weight and depression with adverse pregnancy outcomes are important to recognize in order to focus counselling and care, both before and during pregnancy.

The combined effects of maternal depression and excess weight on neonatal outcomes.

OBJECTIVE: Maternal overweight/obesity and depression are among the most prevalent pregnancy complications, and although individually they are associated with poor pregnancy outcomes, their combined effects are unknown. Owing to this, the objective of this study was to determine the prevalences and the individual and combined effects of depression and overweight/obesity on neonatal outcomes. METHODS: A retrospective cohort study of all singleton hospital births at >20 weeks gestation in Ontario, Canada (April 2007 to March 2010) was conducted. The primary outcome measure was a composite neonatal outcome, which included: stillbirth, neonatal death, preterm birth, birth weight <2500 g, <5% or >95%, admission to a neonatal special care unit, or a 5-min Apgar score <7. RESULTS: Among the 70,605 included women, 49.7% had a healthy pre-pregnancy BMI, whereas 50.3% were overweight/obese; depression was reported in 5.0% and 6.2%, respectively. Individually, depression and excess pre-pregnancy weight were associated with an increased risk of adverse neonatal outcomes, but the highest risk was seen when they were both present (16% of non-depressed healthy weight pregnant women, 19% of depressed healthy weight women, 20% of non-depressed overweight/obese women and 24% of depressed overweight/obese women). These higher risks of adverse neonatal outcomes persisted after accounting for potential confounding variables, such as maternal age, education and pre-existing health problems (adjusted odds ratio (OR) 1.22, 95% confidence interval (CI) 1.13-1.33, adjusted OR 1.23, 95% CI 1.18-1.28 and adjusted OR 1.42, 95% CI 1.31-1.54, in the last three groups above, respectively, relative to non-depressed healthy weight women). There was no significant interaction between weight category and depression (P=0.2956). CONCLUSIONS: When dually present, maternal overweight/obesity and depression combined have the greatest impact on the risk of adverse neonatal outcomes. Our findings have important public health implications given the exorbitant proportions of both of these risk factors.

Women's intentions to breastfeed: a population-based cohort study.

OBJECTIVE: Given that intention to breastfeed is a strong predictor of breastfeeding initiation and duration, the objectives of this study were to estimate the population-based prevalence and the factors associated with the intention to breastfeed. DESIGN: Retrospective population-based cohort study. SETTING: All hospitals in Ontario, Canada (1 April 2009-31 March 2010). POPULATION: Women who gave birth to live, term, singletons/twins. METHODS: Patient, healthcare provider, and hospital factors that may be associated with intention to breastfeed were analysed using univariable and multivariable regression. MAIN OUTCOME MEASURES: Population-based prevalence of intention to breastfeed and its associated factors. RESULTS: The study included 92,364 women, of whom 78,806 (85.3%) intended to breastfeed. The odds of intending to breastfeed were higher amongst older women with no health problems and women who were cared for exclusively by midwives (adjusted OR 3.64, 95% CI 3.13-4.23). Being pregnant with twins (adjusted OR 0.73, 95% CI 0.57-0.94), not attending antenatal classes (adjusted OR 0.58, 95% CI 0.54-0.62), having previous term or preterm births (adjusted OR 0.79, 95% CI 0.78-0.81, and adjusted OR 0.87, 95% CI 0.82-0.93, respectively), and delivering in a level-1 hospital (adjusted OR 0.85, 95% CI 0.77-0.93) were associated with a lower intention to breastfeed. CONCLUSIONS: In this population-based study ~85% of women intended to breastfeed their babies. Key factors that are associated with the intention to breastfeed were identified, which can now be targeted for intervention programmes aimed at increasing the prevalence of breastfeeding and improving overall child and maternal health.

Bleeding disorders, menorrhagia and iron deficiency: impacts on health-related quality of life.

von Willebrand disease (VWD) is a bleeding disorder that occurs in up to 1% of the general population. The great majority of females with VWD experience menorrhagia. The morbidity burden in females with VWD may relate to iron deficiency resulting from menorrhagia. To explore relationships between bleeding disorders, menorrhagia, iron deficiency and the outcomes of health-related quality of life (HRQL) and educational attainment. All subjects with VWD, and females with other bleeding disorders, in the Canadian national registry who were more than 12 years of age were eligible for survey. Survey measures included the HEALTH UTILITIES INDEX(®); abridged Clinical History Assessment Tool; socio-demographic questions and serum ferritin. Statistical analyses included testing differences among groups of means using analysis of variance and of proportions using chi-squared test. Significant size differences in mean HRQL scores were detected between VWD females and both females with other bleeding disorders [diff = (-0.08); P = 0.017] and VWD males [diff = (-0.07); P = 0.039]. Mean HRQL scores differed between females with and without menorrhagia (P < 0.001). Mean HRQL scores were not significantly different between females with and without iron deficiency. Educational attainment was not associated with disease group, menorrhagia status or iron status. Females with VWD have a greater morbidity burden than females in the general population, females with other bleeding disorders and males with VWD. Menorrhagia is associated with low HRQL scores in females with bleeding disorders, including VWD. Further investigation should assess how menorrhagia impacts HRQL in females with bleeding disorders.

Estimating the excess costs for patients with incident fractures, prevalent fractures, and nonfracture osteoporosis.

SUMMARY: Based on a population age 50+, significant excess costs relative to matched controls exist for patients with incident fractures that are similar in relative magnitude to other chronic diseases such as stroke or heart disease. Prevalent fractures also have significant excess costs that are similar in relative magnitude to asthma/chronic obstructive pulmonary disease. INTRODUCTION: Cost of illness studies for osteoporosis that only include incident fractures may ignore the long-term cost of prevalent fractures and primary preventive care. We estimated the excess costs for patients with incident fractures, prevalent fractures, and nonfracture osteoporosis relative to matched controls. METHODS: Men and women age 50+ were selected from administrative records in the province of Manitoba, Canada for the fiscal year 2007-2008. Three types of cases were identified: (1) patients with incident fractures in the current year (2007-2008), (2) patients with prevalent fractures in previous years (1995-2007), and (3) nonfracture osteoporosis patients identified by specific pharmacotherapy or low bone mineral density. Excess resource utilization and costs were estimated by subtracting control means from case means. RESULTS: Seventy-three percent of provincial population age 50+ (52 % of all men and 91 % of all women) were included (121,937 cases, 162,171 controls). There were 3,776 cases with incident fracture (1,273 men and 2,503 women), 43,406 cases with prevalent fractures (15,784 men and 27,622 women) and 74,755 nonfracture osteoporosis cases (7,705 men and 67,050 women). All incident fractures had significant excess costs. Incident hip fractures had the highest excess cost: men $44,963 (95 % CI: $38,498-51,428) and women $45,715 (95 % CI: $36,998-54,433). Prevalent fractures (other than miscellaneous or wrist fractures) also had significant excess costs. No significant excess costs existed for nonfracture osteoporosis. CONCLUSION: Significant excess costs exist for patients with incident fractures and with prevalent hip, vertebral, humerus, multiple, and traumatic fractures. Ignoring prevalent fractures underestimate the true cost of osteoporosis.

Estimation of the lifetime risk of hip fracture for women and men in Canada.

UNLABELLED: In Canada in 2008, based on current rates of fracture and mortality, a woman or man at age 50 years will have a projected lifetime risk of fracture of 12.1% and 4.6%, respectively, and 8.9% and 6.7% after incorporating declining rates of hip fracture and increases in longevity. INTRODUCTION: In 1989, the lifetime risk of hip fractures in Canada was 14.0% (women) and 5.2% (men). Since then, there have been changes in rates of hip fracture and increased longevity. We update these estimates to 2008 adjusted for these trends, and in addition, we estimated the lifetime risk of first hip fracture. METHODS: We used national administrative data from fiscal year April 1, 2007 to March 31, 2008 to identify all hip fractures in Canada. We estimated the crude lifetime risk of hip fracture for age 50 years to end of life using life tables. We projected lifetime risk incorporating national trends in hip fracture and increased longevity from Poisson regressions. Finally, we removed the percentage of second hip fractures to estimate the lifetime risk of first hip fracture. RESULTS: From April 1, 2007 to March 31, 2008, there were 21,687 hip fractures, 15,742 (72.6%) in women and 5,945 (27.4%) in men. For women and men, the crude lifetime risk was 12.1% (95%CI, 12.1, 12.2%) and 4.6% (95%CI, 4.5, 4.7%), respectively. When trends in mortality and hip fractures were both incorporated, the lifetime risk of hip fracture were 8.9% (95%CI, 2.3, 15.4%) and 6.7% (95%CI, 1.2, 12.2%). The lifetime risks for first hip fracture were 7.3% (95%CI, 0.8, 13.9%) and 6.2% (95%CI, 0.7, 11.7%). CONCLUSIONS: The lifetime risk of hip fracture has fallen from 1989 to 2008 for women and men. Adjustments for trends in mortality and rates of hip fracture with removing second fractures produced non-significant differences in estimates.

Life insurance for living kidney donors: a Canadian undercover investigation.

Some living kidney donors encounter difficulties obtaining life insurance, despite previous surveys of insurance companies reporting otherwise. To better understand the effect of donation on insurability, we contacted offices of life insurance companies in five major cities in Canada to obtain $100 000 of life insurance (20-year term) for 40 fictitious living kidney donors and 40 paired controls. These profiles were matched on age, gender, family history of kidney disease and presence of hypertension. The companies were blinded to data collection. The study protocol was reviewed by the Office of Research Ethics. The main study outcomes were the annual premium quoted and total time spent on the phone with the insurance agent. All donor and control profiles received a quote, with no significant difference in the premium quoted (medians $190 vs. $209, p = 0.89). More time was spent on the phone for donor compared to control profiles, but the absolute difference was small (medians 9.5 vs. 7.0 min, p = 0.046). Age, gender, family history of kidney disease and new-onset hypertension had no further effect on donor insurability in regression analysis. We found no evidence that kidney donors were disadvantaged in the first step of applying for life insurance. The effect donation has on subsequent phases of insurance underwriting remains to be studied.