Shape Of Dose-response Relationship Research Articles

Shape of radiation dose response relationship for ischaemic heart disease mortality and its interpretation: analysis of the national registry for radiation workers (NRRW) cohort

Statistically significant increases in ischemic heart disease (IHD) mortality with cumulative occupational external radiation dose were observed in the National Registry for Radiation Workers (NRRW) cohort. There were 174 541 subjects in the NRRW cohort. The start of follow up was 1955, and the end of the follow-up for each worker was chosen as the earliest date of death or emigration, their 85th birthday or 31 December 2011. The dose-response relationship showed a downward curvature at a higher dose level >0.4 Sv with the overall shape of the dose-response relationship best described by a linear-quadratic model. The smaller risk at dose >0.4 Sv appears to be primarily associated with workers who started employment at a younger age (<30 years old) and those who were employed for more than 30 years. We modelled the dose response by age-at-first exposure. For the age-at-first exposure of 30+ years old, a linear dose-response was the best fit. For age-at-first exposure <30 years old, there was no evidence of excess risk of IHD mortality for radiation doses below 0.1 Sv or above 0.4 Sv, excess risk was only observed for doses between 0.1–0.4 Sv. For this age-at-first exposure group, it was also found that the doses they received when they were less than 35 years old or greater than 50 years old did not contribute to any increased IHD risk.

Skipping a pillar does not make for strong foundations: Pharmacokinetic-pharmacodynamic reasoning behind the shape of dose-response relationships in oncology.

Dose-response analysis is often applied to the quantification of drug-effect especially for slowly responding disease end points where a comparison is made across dose levels after a particular period of treatment. It has long been recognized that exposure - response is more appropriate than dose-response. However, trials necessarily are designed as dose-response experiments. Second, a wide range of functional forms are used to express relationships between dose and response. These considerations are also important for clinical development because pharmacokinetic (PK; and variability) plus pharmacokinetic-pharmacodynamic modeling may allow one to anticipate the shape of the dose-response curve and so the trial design. Here, we describe how the location and steepness of the dose response is determined by the PKs of the compound being tested and its exposure-response relationship in terms of potency (location), efficacy (maximum effect) and Hill coefficient (steepness). Thus, the location (50% effective dose [ED50 ]) is dependent not only on the potency (half-maximal effective concentration) but also the compound's PKs. Similarly, the steepness of the dose response is shown to be a function of the half-life of the drug. It is also shown that the shape of relationship varies dependent on the assumed time course of the disease. This is important in the context of drug-discovery where the in vivo potencies of compounds are compared as well as when considering an analysis of summary data (for example, model-based meta-analysis) for clinical decision making.

Abstract P219: Central Obesity and All-cause and Cause Specific Mortality: a Systematic Review and Dose-response Meta-analysis of Prospective Studies

Background: The association of central obesity and mortality risk has not been systematically investigated. The strength and shape of dose-response relationship between central obesity and all-cause and cause specific mortality still remains unclear. Therefore, we conducted a systematic review and meta-analysis to clarify the associations. Methods: Categorical and dose-response meta-analysis was conducted involving of prospective studies. PubMed and Embase were searched up to April 1st, 2017 for eligible studies of waist circumference, waist-to-hip ratio and all-cause and cause specific mortality. Random-effects models were used to derive the summary relative risks (RRs) and corresponding 95% CI for specific categories of central obesity and a continuous association using generalized least-squares trend estimation. Results: A total of 1 760 947 participants in 50 studies were included in the meta-analysis. The pooled RRs for a 10 cm increase in waist circumference were 1.06 (95% CI, 1.04-1.08; I 2 =92.9%), 1.06 (95% CI, 1.03-1.08; I 2 =90.9%), 1.21 (95% CI, 1.06-1.35; I 2 =88.1%) and 1.05 (95% CI, 1.02-1.08; I 2 =86.5%) for all-cause, cardiovascular disease (CVD), coronary heart disease (CHD), and cancer mortality, respectively. We found a nonlinear relationship between waist circumference and all-cause mortality among both women (p&lt;0.001) and men (p=0.011). The summary RRs for a 0.1 unit in waist-to-hip ratio were 1.17 (95% CI, 1.12-1.21; I 2 =88.2%), 1.26 (95% CI, 1.17-1.34; I 2 =66.3%), 1.25 (95% CI, 1.10-1.40; I 2 =67.8%) and 1.13 (95% CI, 1.09-1.16; I 2 =0.0%) for all-cause, CVD, CHD, and cancer mortality, respectively. There was evidence of a nonlinear relationship between waist-to-hip ratio and all-cause mortality among women (p=0.016) rather than men (p=0.424). The dose-response relationship between central obesity and cause specific mortality were linear, except the association of waist circumference and CVD mortality (p=0.037), and waist-to-hip ratio and cancer mortality (p=0.039). Conclusions: Higher waist circumference and waist-to-hip ratio measured continuously and categorically, increase the risk of all-cause mortality among men and women and are associated with increased risk of CVD, CHD and cancer mortality.

Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship.

Background and objectiveWalking and cycling have shown beneficial effects on population risk of all-cause mortality (ACM). This paper aims to review the evidence and quantify these effects, adjusted for other physical activity (PA).Data sourcesWe conducted a systematic review to identify relevant studies. Searches were conducted in November 2013 using the following health databases of publications: Embase (OvidSP); Medline (OvidSP); Web of Knowledge; CINAHL; SCOPUS; SPORTDiscus. We also searched reference lists of relevant texts and reviews.Study eligibility criteria and participantsEligible studies were prospective cohort design and reporting walking or cycling exposure and mortality as an outcome. Only cohorts of individuals healthy at baseline were considered eligible.Study appraisal and synthesis methodsExtracted data included study population and location, sample size, population characteristics (age and sex), follow-up in years, walking or cycling exposure, mortality outcome, and adjustment for other co-variables. We used random-effects meta-analyses to investigate the beneficial effects of regular walking and cycling.ResultsWalking (18 results from 14 studies) and cycling (8 results from 7 studies) were shown to reduce the risk of all-cause mortality, adjusted for other PA. For a standardised dose of 11.25 MET.hours per week (or 675 MET.minutes per week), the reduction in risk for ACM was 11% (95% CI = 4 to 17%) for walking and 10% (95% CI = 6 to 13%) for cycling. The estimates for walking are based on 280,000 participants and 2.6 million person-years and for cycling they are based on 187,000 individuals and 2.1 million person-years. The shape of the dose–response relationship was modelled through meta-analysis of pooled relative risks within three exposure intervals. The dose–response analysis showed that walking or cycling had the greatest effect on risk for ACM in the first (lowest) exposure interval.Conclusions and implicationsThe analysis shows that walking and cycling have population-level health benefits even after adjustment for other PA. Public health approaches would have the biggest impact if they are able to increase walking and cycling levels in the groups that have the lowest levels of these activities.Review registrationThe review protocol was registered with PROSPERO (International database of prospectively registered systematic reviews in health and social care) PROSPERO 2013: CRD42013004266.Electronic supplementary materialThe online version of this article (doi:10.1186/s12966-014-0132-x) contains supplementary material, which is available to authorized users.

MIXTURE TOXICITY OF COPPER AND DIAZINON TO LARVAE OF THE MAYFLY (EPHORON VIRGO) JUDGING ADDITIVITY AT DIFFERENT EFFECT LEVELS

The toxic unit concept is commonly applied for determining the effects of a mixture of toxicants. Use of this concept is, however, limited to compounds with similarly shaped dose-response relationships. In the present study, a method is proposed to gain insight regarding the influence of differences in the shapes of dose-response relationships on the applicability of the concentration-addition model by judging additivity at different effect levels. To this purpose, two model toxicants with different modes of action and dose-response relationships were selected: copper, and diazinon. Using mortality of the mayfly (Ephoron virgo) as the endpoint, it was demonstrated that the two compounds act in a less-than-concentration-additive manner. Application of the proposed calculation method revealed that the less-than-concentration-addition effect was independent of the effect level on which the mixture was judged.