True Biological Effect Research Articles

Nonproportional Hazards and the Power of Sequential Trials

Although statistical methods exist for the calculation of sample size and for the analysis of standard endpoint trials with nonproportional hazards, the impact of nonproportional hazards on the properties of sequential clinical trials has not been well studied. In this article we use simulation to evaluate the impact of nonproportional hazards on the power of standard group sequential methods. We consider boundaries designed to reject H0 only, H1 only, or both H0 and H1.Key findings include: (1) The presence of onset lag causes a greater decrease in the power of a sequential method than the power of the fixed-sample method. The impact is particularly great on sequential methods that allow for early rejection of H1; in some cases, the power of these methods may have a ceiling that cannot be crossed regardless of the true biologic effect of the treatment. (2) The presence of noncompliance (as measured by permanent discontinuation of study medication) causes a smaller impact on the power of a sequential method than on the power of the fixed-sample method. In fact, when the rate of noncompliance is high, sequential methods, particularly those that allow early rejection of H0, can have greater power than a fixed-sample approach.

Statistical considerations for a phase 0 trial

14038 Background: Phase ‘0’ clinical trials are small first in man studies to determine a dose or dose range which results in a desired biologic effect. Novel statistical designs are needed due to the limited number of patients and the complexities of analyzing primary pharmacodynamic endpoints. Methods: In general, the effect of the agent will be evaluated, based on a biologic endpoint(s), at two levels, the individual participant level (for a given dose amount), and the agent dose amount level (across individual participants). At the participant level, the effect is preferably defined as a dichotomous outcome. The statistical criteria should be such that the threshold is not surpassed with more than .10 probability, for a given participant, at a given dose amount, for the null hypothesis case of no true biologic effect. At the dose amount level, the effect rate is defined as the probability that a randomly chosen participant will satisfy the participant level threshold. The statistical criteria for declaring an observed effect rate to be significant should be such that the over-all probability of declaring the agent effective (summed across all dose amounts) should not exceed .10 for the null hypothesis case of no true biologic effect. A target effect rate, measured across participants, should be given, and the power to detect it, for a given dose amount, should be estimated. Ideally, there will be multiple pre-agent administration endpoint measurements, per participant, to define variability. Examples: 1. If 10 participants are accrued to a single dose amount, an observed effect rate for that dose amount could be defined to be significant if at least 2 of the 10 participants satisfy the participant threshold, yielding 85–90% power to detect a 35% effect rate. 2. If 5 participants are accrued to each of 2 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 5 participants satisfy the participant threshold, yielding approximately 90% power to detect a 60% effect rate. 3. If 3 participants are accrued to each of 4 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 3 participants satisfy the participant threshold, yielding approximately 90% power to detect an 80% effect rate. No significant financial relationships to disclose.

Aspects of anthocyanin absorption, metabolism and pharmacokinetics in humans

Interest in the health-promoting properties of berry anthocyanins is intensifying; however, findings are primarily based on in vitro characteristics, leaving mechanisms associated with absorption, metabolism and pharmacokinetics largely unexplored. The present review integrates the available anthocyanin literature with that of similar flavonoids or polyphenols in order to form hypotheses regarding absorption, metabolism and clearance in humans. Of the limited available literature regarding the absorption and clearance kinetics of anthocyanins, maximum plasma concentrations are reported anywhere between 1.4 and 592 nmol/l and occur at 0.5-4 h post-consumption (doses; 68-1300 mg). Average urinary excretion is reported between 0.03 and 4 % of the ingested dose, having elimination half-lives of 1.5-3 h. In addition, much is unknown regarding the metabolism of anthocyanins. The most commonly cited conjugation reactions involved in the metabolism of other flavonoids include glucuronidation, methylation and sulfation. It is reasonable to suspect that anthocyanins are metabolised in much the same manner; however, until recently, there was little evidence to suggest that anthocyanins were metabolised to any significant extent. New evidence now suggests that anthocyanins are absorbed and transported in human serum and urine primarily as metabolites, with recent studies documenting as much as 68-80 % of anthocyanins as metabolised derivatives in human urine. Further research is required to resolve mechanisms associated with the absorption, metabolism and clearance of anthocyanins in order to establish their true biological activities and health effects. The presented evidence will hopefully focus future research, refining study design and propagating a more complete understanding of anthocyanins' biological significance in humans.

Complementary and Alternative Therapies for Women Transitioning through Menopause

Objective: Women beginning the transition to menopause now have access to complementary and alternative therapies (CAM) that were not universally available in the past. Little is known about the association between CAM use and the use of conventional health care during menopause. Therefore, knowledge of CAM therapies is becoming necessary for physical therapists as it has potential impact on rehabilitation outcomes. This article presents the prevalence of the use of complementary and alternative medicine (CAM) in women in menopause and evidence for the use of these various therapies throughout the available scientific literature. Methods: Scientific articles were identified by searching MEDLINE, CINAHL, and HEALTH databases from 1995 to 2006 for English-language articles using the key terms menopause and complementary and alternative medicine or therapy. Sixty-nine references were reviewed; 61 were selected for citation based on specific reference to CAM for symptoms commonly attributed to menopause. Results: Study designs of the 61 articles included 14 cross sectional studies, 8 randomized controlled trials, 3 longitudinal studies, 5 cohort studies, 2 meta-analyses, 2 pilot studies, and 1 summary of committee proceedings, as well as 26 review articles. The scientific literature was categorized under the headings: nutritional supplements, herbal remedies, homeopathic remedies, and physical approaches. Some scientific evidence of the safety and efficacy of alternative treatments during menopause was uncovered, with the strongest evidence emerging in favor of phytoestrogens, which occur in high concentrations as isoflavones in soy products. There is a paucity of research, especially randomized controlled trials (RCT), regarding the true biological effect of CAM for women experiencing menopause. Conclusions: Randomized controlled trials, standardization of dosage, and accurate safety and efficacy labeling are required to ensure proper use of CAM. Physical therapists need to be aware of herbdrug interactions during rehabilitation treatment. Further research is necessary to determine the efficacy, safety, and effectiveness of CAM in these women.

Influence of aetiological factors for breast cancer on outcome after diagnosis

762 Background: Risk factors which influence the incidence of breast cancer may also affect survival after diagnosis. Methods: We studied the prognostic effects of reproductive history, height, weight, body mass index (BMI), smoking history, alcohol intake and prior use of the combined oral contraceptive pill (COC) and hormonal replacement therapy (HRT) in 4816 women who had taken part in the population-based SEARCH-breast cancer study. Hazard ratios (HRs) for death (all causes) were estimated using Cox proportional hazards survival model for each risk factor. Multivariate analysis was performed adjusting for grade, stage and age at diagnosis. Results: Median follow up was 5.27 years. On univariate analysis, reproductive history, age at menarche and menopause, menopause status at diagnosis, smoking history, prior use of HRT and COC were not seen to influence prognosis. Tumour grade and stage had a highly significant impact on overall survival (p<0.0001). Increasing height and decreasing weight were associated with a decreased risk of death. BMI was associated with a HR for death of 1.03 (95%CI 1.02–1.05; p=0.0002) per unit increase. Women who were in the highest quartile of BMI were 1.6 times more likely to die (95%CI 1.2–2.0) than those in the lowest quartile. Improved prognosis was seen with increasing current alcohol consumption. The HR for death was 0.98 per unit alcohol consumed per week (95%CI 0.96–0.99; p=0.0043); intake of 14 or more units was associated with a HR of 0.69 (95%CI 0.49–0.96). Previous alcohol intake did not significantly affect outcome. The effects of BMI and current alcohol consumption were not attenuated after adjusting for grade and stage. However, the effect of alcohol intake was marginally significant at the 5% level after adjusting for multiple comparisons. Conclusions: Our finding that an increase in BMI is associated with a negative impact on survival supports previously published data. The apparent benefit of alcohol intake has not been described before. Other studies have either shown no effect or poorer outcome in heavy drinkers. Our findings are preliminary and may simply be due to chance or confounding; or may reflect a true biological effect. Further work is needed to clarify these alternatives. No significant financial relationships to disclose.

Does insufficient adjustment for smoking explain the preventive effects of fruit and vegetables on lung cancer?

Recent reports have raised the question, whether the previously observed protective effects of high intake of fruit and vegetables on the risk of lung cancer were due to insufficient adjustment for smoking leading to residual confounding. Association of intake of fruit and vegetables on lung cancer risk was examined, using the Danish prospective cohort study, “Diet, Cancer and Health”. Participants completed a food-frequency and lifestyle questionnaire, and age-standardized incidence rates and rate ratios were estimated for quartiles of dietary exposure. In 1993–2001, 247 out of the 54 158 participants were diagnosed with lung cancer. The incidence rate of lung cancer was highest in the lowest quartile of intake of plant food (fruit, vegetables, legumes and potatoes) and the age-standardized rate ratio of lung cancer decreased significantly with increasing intake of plant food to 0.35 (95% CI, 0.27–0.45) but after control for smoking it was attenuated to 0.65 (95% CI, 0.45–0.93). The incidence rate differences of current smokers with high (≥400 g per day) and low (<400 g per day) daily intake of plant food were independent of smoking intensity; assuming a true biological protective effect, 80–90 lung cancer cases per 100 000 current smokers could be prevented in our cohort if all smokers had a high intake of plant food. The observed inverse association between high intakes of plant food seems chiefly to be a real protective effect, and not solely due to residual confounding.

The importance of effect mechanism in the design and interpretation of clinical trials: The role of magnesium in acute myocardial infarction

The design and interpretation of randomized clinical trials and of meta-analyses of trials should be informed by a biologically plausible hypothesis of treatment effect. Without some insight on likely mechanism, trial conditions may not be optimum to allow a true treatment effect to be detected. Judgments on mechanism underpin decisions on the appropriateness of pooling studies in meta-analysis. Where statistical heterogeneity of trial results is found, the possibility of true biological effect modification can only be assessed by considering potential treatment mechanisms. These can then be tested in carefully designed laboratory models. Meta-analysis of 12 randomized controlled trials of intravenous Mg 2+ in acute myocardial infarction gives a null effect (odds ratio 1.02, 95% CI 0.96 to 1.08) with a fixed effects model, but with strong evidence of heterogeneity (P < .0001) due to a single large study in which Mg 2+ was generally given late and after fibrinolytic treatment. A random effects model gives a pooled odds ratio 0.61 (95% CI 0.43 to 0.87, P = 0.006). Laboratory models show that timing of Mg 2+ administration before or after reperfusion critically determines whether myocardial protection occurs. Copyright 2002, Elsevier Science (USA). All rights reserved.

The effect of breastfeeding on child development at 5 years: a cohort study.

It is uncertain to what degree the relationship between breastfeeding and later cognitive development is a true biological effect, or is confounded by psychosocial factors. The study aim was to further investigate this relationship and the effect of duration of breast feeding on cognitive development. A total of 3880 children were followed from birth. Breastfeeding duration was measured by questionnaire at 6 months of age and a Peabody Picture Vocabulary Test Revised (PPVT-R) was administered at 5 years. PPVT-R scores were adjusted for the effects of a large array of biological and psychosocial confounders. The relationship between breastfeeding and the mean PPVT-R scores were examined using analysis of variance and multiple linear regression. A strong positive relationship was demonstrated between breastfeeding and the PPVT-R scores with increasing scores with increased duration of breastfeeding. After adjusting for a wide range of biological and social factors, the adjusted mean for those breastfed for 6 months or more was 8.2 points higher for females and 5.8 points for males when compared to those never breastfed. These findings suggest a significant benefit to child development is conferred by breastfeeding and is related independently to longer periods of breastfeeding.

Microbial biomass dynamics following addition of metal-enriched sewage sludges to a sandy loam

The short-and long-term effects of additions of sewage sludge enriched, or not, with the single metals Zn, Cu, Ni or Cd, on soil microbial biomas and microbial activities were studied following incubation under laboratory conditions (25°C, 50% WHC). The unenriched (low-metal) and metal-enriched (high-metal) sludges were added separately at four rates so that total soil concentrations of each metal were between 1–4 times the European Union (EU) current permitted limits. The main aim was to determine the minimum scil concentrations at which individual metals added in sewage sludge caused a decline in the amount or activity of the soil microbial biomass. Sludge addition increased biomass C by about 30% at the lowest rate of application (40 t ha −1) and about 4.5-fold at the highest rate (160 t ha −1) after 4 wk of incubation, irrespective of whether the sludges were metal-enriched or not. However, during the longer 64-wk incubation, the amounts of microbial biomass declined exponentially. larger applications of high-metal sludges caused final biomasses which were smaller than those both in soils given no sludge and low-metal sludge. None of the metals at about the currently permitted EU soil limits showed any adverse effects on microbial biomass. However, Zn, Cu or Cd individually at about twice the EU limits decreased biomass C by about 20%, whereas Ni at 4 times the limit decreased the biomass by about 15%. The amounts of metals extracted with 0.5 m K 2SO 4 increased both with increasing sludge application rates and with prolonged incubation, but different proportions of each metal were extracted. The extractability decreased in the order Cd > Zn > Ni > Cu. The amounts of inorganic N in the control soil increased with prolonged incubation. However, inorganic N in all the soils treated with sludge declined to practically zero after 4 wk, presumably due to immobilization or denitrification. After this initial decline, soil inorganic N increased steadily until the incubation ended. Averaged over the four sludge application rates, the accumulation of inorganic N was greatest in the soils which received low-metal sludge, closely followed by Cd-sludged soils and was least in the Zn-sludged soils. This suggests that the relative toxicity of the heavy metals towards N mineralization after 64 wk was Zn>Ni>Cu⪢Cd. There were close positive correlations between biomass C and dehydrogenase activity in all the soils that received sludge, although dehydrogenase activity was about one-fourth in the soils that received high-Cu sludge. This was attributed to an artefact in the methodology rather than a true biological effect.

The Relationship of Milk Somatic Cell Count to Milk Yields for Holstein Heifers After First Calving

The contribution of a dilution effect to the relationship between milk yield and milk SCC was investigated using data from 24 Holsteins during the first 75 d after first calving. Bucket and quarter milk SCC were collected at weekly intervals. Individual milk weights were obtained at milking, and samples were obtained for determination of SCC. The milk weights at the corresponding a.m. milking on the following day were also obtained. A dilution effect was assumed to cause the regression of milk yield on milk SCC to diminish when adjustment was made for milk yield on the day following sampling for SCC. Regressions of milk yield on various functions of SCC decreased by about one-half when adjustment was made for the next day's milk yield, but the regressions remained significant. The observed negative relationship between milk yield and SCC may partly reflect both the true biological effects of udder inflammation and a dilution effect. The carry-over effect of SCC on milk yields measured 1 wk after cell counting was investigated, but no effect was significant.

Inhibition of follicle-stimulating hormone induction of aromatase activity in porcine granulosa cells by thyroxine and triiodothyronine.

We examined the effects of T3 and T4 on basal and FSH-induced aromatase activity in granulosa cells isolated from medium-sized follicles (4-6 mm) of prepubertal pigs. Treatment of cells with T3 or T4 alone during an initial 48-h induction period did not result in any significant change in aromatase activity, as measured by 17 beta-estradiol accumulation during the subsequent 6-h test period, when testosterone (0.5 microM) was added as substrate. However, when cells were cultured with FSH and T3 or T4 during the induction period, a definite dose-dependent inhibition of FSH-induced aromatase activity was demonstrated. This inhibition was not altered by the presence of a binding protein (BSA). The inhibition of FSH-induced aromatase activity by T4 and T3 is a true biological effect, as inactive iodocompounds (MIT and DIT) and iodide had no significant effect on the gonadotropin-induced aromatase activity. Furthermore, the viability of cells was unaffected by the thyroid hormones, and total cellular protein did not change significantly. These results indicate that thyroid hormones might play an important role in modulating FSH-induced aromatase activity, and that the elevated plasma estrogen levels in some cases of hyperthyroidism are not due to increased ovarian secretion.