Association between antibody titers and protection against influenza virus infection within households.

BACKGROUND: Previous studies have established that antibody titer measured by the hemagglutination-inhibiting (HAI) assay is correlated with protection against influenza virus infection, with an HAI titer of 1:40 generally associated with 50% protection. METHODS: We recruited index cases with confirmed influenza virus infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. Serum samples collected from a subset of household contacts were tested by HAI and microneutralization (MN) assays against prevalent influenza viruses. We analyzed the data using an individual hazard-based transmission model that adjusted for age and vaccination history. RESULTS: Compared to a reference group with antibody titers <1:10, we found that HAI titers of 1:40 against influenza A(H1N1) and A(H3N2) were associated with 31% (95% confidence interval [CI], 13%-46%) and 31% (CI, 1%-53%) protection against polymerase chain reaction (PCR)-confirmed A(H1N1) and A(H3N2) virus infection, respectively, while an MN titer of 1:40 against A(H3N2) was associated with 49% (95% CI, 7%-81%) protection against PCR-confirmed A(H3N2) virus infection. CONCLUSIONS: An HAI titer of 1:40 was associated with substantially less than 50% protection against PCR-confirmed influenza virus infection within households, perhaps because of exposures of greater duration or intensity in that confined setting.

Power and sample size calculations for Mendelian randomization studies using one genetic instrument.

Mendelian randomization, which is instrumental variable analysis using genetic variants as instruments, is an increasingly popular method of making causal inferences from observational studies. In order to design efficient Mendelian randomization studies, it is essential to calculate the sample sizes required. We present formulas for calculating the power of a Mendelian randomization study using one genetic instrument to detect an effect of a given size, and the minimum sample size required to detect effects for given levels of significance and power, using asymptotic statistical theory. We apply the formulas to some example data and compare the results with those from simulation methods. Power and sample size calculations using these formulas should be more straightforward to carry out than simulation approaches. These formulas make explicit that the sample size needed for Mendelian randomization study is inversely proportional to the square of the correlation between the genetic instrument and the exposure and proportional to the residual variance of the outcome after removing the effect of the exposure, as well as inversely proportional to the square of the effect size.

Simulated growth trajectories and blood pressure in adolescence: Hong Kong's Chinese Birth Cohort.

BACKGROUND: Patterns and amounts of growth may determine adult blood pressure. Growth at different phases is correlated and affects current size, making effects on blood pressure difficult to distinguish. We decomposed growth to 13 years into independent associations with blood pressure and estimated how reaching the same size by different routes could affect adolescent blood pressure. METHODS: Using estimates from partial least squares for the associations of birth weight, height, and BMI at 3 months, growth at 3-9 months, 9-36 months, 3-8 years and 8-13 years and size at 13 years with SBP and DBP in 5247 term births (67% follow-up) from Hong Kong's 'Children of 1997' Birth Cohort, we estimated SBP and DBP at 13 years for 99 simulated growth trajectories resulting in the same size using nonparametric bootstrapping. RESULTS: High birth weight followed by slower growth was associated with lower SBP in both sexes and DBP in boys. Greater height to 3 years followed by slower height growth was associated with lower SBP in boys. Higher BMI until 9 months followed by slower BMI growth was associated with lower blood pressure in boys. CONCLUSION: High birth weight or larger early size was associated with lower blood pressure if followed by slower later growth, consistent with the fetal origin hypothesis. However, whether these patterns are due to fetal and infant metabolic programming or to allowing slower growth at periods when rapid growth is harmful is unknown.

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.

BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone. METHODS: A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13). CONCLUSIONS: Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.

Cost-effectiveness analysis at the development phase of a potential health technology: examples based on tissue engineering of bladder and urethra.

OBJECTIVES: We demonstrate the use of health economics to guide investment decisions in regenerative medicine. Our examples are based on proposed tissue engineering applications in the urinary tract. We show that health economics have a role in strengthening the supply side, not just the demand side of the health economy. METHODS: We reviewed the epidemiology and treatment of the clinical conditions where TE of urothelium may be considered using literature identified from a range of sources including electronic databases, article bibliographies and references, online articles and expert opinion in the field. RESULTS: Careful analysis of current best treatment suggested that urethral defects and bladder resection for cancer offered the most propitious applications of TE. The headroom for engineered urethral tissue was estimated at pound sterling186. This is unlikely to be large enough to support the launch of a TE product populated with viable cells. The headroom for TE bladder, on the other hand, was estimated at around pound sterling16 268. However, the market size is limited reducing potential profitability. CONCLUSIONS: The Headroom Method can help inform instrumental decisions concerning new treatments without having to build a complex model with very wide parameter uncertainty.

Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapy.

OBJECTIVES: Ongoing developments in design have improved the outlook for left-ventricular assist device (LVAD) implantation as a therapy in end-stage heart failure. Nevertheless, early cost-effectiveness assessments, based on first-generation devices, have not been encouraging. Against this background, we set out (i) to examine the survival benefit that LVADs would need to generate before they could be deemed cost-effective; (ii) to provide insight into the likelihood that this benefit will be achieved; and (iii) from the perspective of a healthcare provider, to assess the value of discovering the actual size of this benefit by means of a Bayesian value of information analysis. METHODS: Cost-effectiveness assessments are made from the perspective of the healthcare provider, using current UK norms for the value of a quality-adjusted life-year (QALY). The treatment model is grounded in published analyses of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial of first-generation LVADs, translated into a UK cost setting. The prospects for patient survival with second-generation devices is assessed using Bayesian prior distributions, elicited from a group of leading clinicians in the field. RESULTS: Using established thresholds, cost-effectiveness probabilities under these priors are found to be low (approximately .2 percent) for devices costing as much as 60,000 pounds. Sensitivity of the conclusions to both device cost and QALY valuation is examined. CONCLUSIONS: In the event that the price of the device in use would reduce to 40,000 pounds, the value of the survival information can readily justify investment in further trials.