Analysis of continuous covariables in epidemiological studies: Dose-response modelling and confounder adjustment

20 years ago, 3 manuscripts describing doses and potential cancer risks from CT scans in children raised awareness of a growing public health problem. We reviewed the epidemiological studies that were initiated in response to these concerns that assessed cancer risks from CT scans using medical record linkage. We evaluated the study methodology and findings and provide recommendations for optimal study design for new efforts. We identified 17 eligible studies; 13 with published risk estimates, and 4 in progress. There was wide variability in the study methodology, however, which made comparison of findings challenging. Key differences included whether the study focused on childhood or adulthood exposure, radiosensitive outcomes (e.g. leukemia, brain tumors) or all cancers, the exposure metrics (e.g. organ doses, effective dose or number of CTs) and control for biases (e.g. latency and exclusion periods and confounding by indication). We were able to compare results for the subset of studies that evaluated leukemia or brain tumors. There were eight studies of leukemia risk in relation to red bone marrow (RBM) dose, effective dose or number of CTs; seven reported a positive dose–response, which was statistically significant (p < 0.05) in four studies. Six of the seven studies of brain tumors also found a positive dose–response and in five, this was statistically significant. Mean RBM dose ranged from 6 to 12 mGy and mean brain dose from 18 to 43 mGy. In a meta-analysis of the studies of childhood exposure the summary ERR/100 mGy was 1.78 (95%CI: 0.01–3.53) for leukemia/myelodisplastic syndrome (n = 5 studies) and 0.80 (95%CI: 0.48–1.12) for brain tumors (n = 4 studies) (p-heterogeneity >0.4). Confounding by cancer pre-disposing conditions was unlikely in these five studies of leukemia. The summary risk estimate for brain tumors could be over estimated, however, due to reverse causation. In conclusion, there is growing evidence from epidemiological data that CT scans can cause cancer. The absolute risks to individual patients are, however, likely to be small. Ongoing large multicenter cohorts and future pooling efforts will provide more precise risk quantification.

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Advancing risk assessment: mechanistic dose–response modelling of Listeria monocytogenes infection in human populations

Royal Society Open Science ◽

10.1098/rsos.180343 ◽

2018 ◽

Vol 5 (8) ◽

pp. 180343 ◽

Cited By ~ 5

Author(s):

Ashrafur Rahman ◽

Daniel Munther ◽

Aamir Fazil ◽

Ben Smith ◽

Jianhong Wu

Keyword(s):

Listeria Monocytogenes ◽

Dose Response ◽

Geometric Interpretation ◽

Human Populations ◽

Response Curves ◽

Future Experimentation ◽

Limited Power ◽

Mechanistic Basis ◽

Response Modelling

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose–response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen–host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose–response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen–immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose–response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

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Bayesian hierarchical dose-response meta-analysis of epidemiological studies: Modeling and target population prediction methods

Environment International ◽

10.1016/j.envint.2020.106111 ◽

2020 ◽

Vol 145 ◽

pp. 106111 ◽

Cited By ~ 1

Author(s):

Bruce Allen ◽

Kan Shao ◽

Kevin Hobbie ◽

William Mendez ◽

Janice S. Lee ◽

...

Keyword(s):

Dose Response ◽

Meta Analysis ◽

Target Population ◽

Epidemiological Studies ◽

Prediction Methods ◽

Bayesian Hierarchical ◽

Population Prediction

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Evaluation of the 50% Infectious Dose of Human Norovirus Cin-2 in Gnotobiotic Pigs: A Comparison of Classical and Contemporary Methods for Endpoint Estimation

Viruses ◽

10.3390/v12090955 ◽

2020 ◽

Vol 12 (9) ◽

pp. 955

Author(s):

Ashwin K. Ramesh ◽

Viviana Parreño ◽

Philip J. Schmidt ◽

Shaohua Lei ◽

Weiming Zhong ◽

...

Keyword(s):

Dose Response ◽

Response Models ◽

Infectious Dose ◽

Clinical Data Analysis ◽

Causative Agents ◽

Gnotobiotic Pigs ◽

Gnotobiotic Pig ◽

Response Modelling ◽

Sporadic Acute Gastroenteritis ◽

Endpoint Estimation

Human noroviruses (HuNoVs) are the leading causative agents of epidemic and sporadic acute gastroenteritis that affect people of all ages worldwide. However, very few dose–response studies have been carried out to determine the median infectious dose of HuNoVs. In this study, we evaluated the median infectious dose (ID50) and diarrhea dose (DD50) of the GII.4/2003 variant of HuNoV (Cin-2) in the gnotobiotic pig model of HuNoV infection and disease. Using various mathematical approaches (Reed–Muench, Dragstedt–Behrens, Spearman–Karber, logistic regression, and exponential and approximate beta-Poisson dose–response models), we estimated the ID50 and DD50 to be between 2400–3400 RNA copies, and 21,000–38,000 RNA copies, respectively. Contemporary dose–response models offer greater flexibility and accuracy in estimating ID50. In contrast to classical methods of endpoint estimation, dose–response modelling allows seamless analyses of data that may include inconsistent dilution factors between doses or numbers of subjects per dose group, or small numbers of subjects. Although this investigation is consistent with state-of-the-art ID50 determinations and offers an advancement in clinical data analysis, it is important to underscore that such analyses remain confounded by pathogen aggregation. Regardless, challenging virus strain ID50 determination is crucial for identifying the true infectiousness of HuNoVs and for the accurate evaluation of protective efficacies in pre-clinical studies of therapeutics, vaccines and other prophylactics using this reliable animal model.

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Relationships and Mechanisms Between Occupational Risk Factors and Distal Upper Extremity Disorders

Human Factors The Journal of the Human Factors and Ergonomics Society ◽

10.1177/0018720819860683 ◽

2019 ◽

pp. 001872081986068 ◽

Cited By ~ 5

Author(s):

Peter J. Keir ◽

Amanda Farias Zuniga ◽

Daanish M. Mulla ◽

Kumara G. Somasundram

Keyword(s):

Risk Factors ◽

Upper Extremity ◽

Dose Response ◽

Injury Risk ◽

Epidemiological Studies ◽

Task Demands ◽

Laboratory Studies ◽

Occupational Risk Factors ◽

Upper Extremity Disorders ◽

Extremity Injuries

Objective:The relationships between workplace risk factors and upper extremity injuries from epidemiological and laboratory studies were examined.Background:Epidemiological studies are associated with several limitations, affecting the strength of association between risk factors and the development of injuries.Method:In this narrative review, we identified epidemiological and laboratory studies (published primarily since 1997) investigating exposure to workplace risk factors (force, repetition, posture, vibration) and risk of hand/wrist tendon–related disorders, epicondylitis, and carpal tunnel syndrome (CTS).Results:Forceful exertions are strongly associated with hand/wrist tendon–related disorders, epicondylitis, and CTS. Dose–response relationships were found for epicondylitis (repetition) and CTS (posture). Interactions demonstrate multiplicative effects of risk factors for injury risk. Laboratory studies display clear associations between task demands and biomechanical measures linked to mechanisms for upper extremity injuries with animal models providing further evidence of a dose–response between risk factors and injury.Conclusion:Forceful, repetitive work requiring non-neutral postures are associated with increasing risk of hand/wrist tendon–related disorders, epicondylitis, and CTS as evidenced by epidemiology studies and laboratory-based investigations of humans and animals.Application:Understanding the relationship between exposure levels of workplace risk factors and upper extremity disorders can improve injury prevention and rehabilitation strategies.

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On combining dose—response data from epidemiological studies by meta-analysis

Statistics in Medicine ◽

10.1002/sim.4780140513 ◽

1995 ◽

Vol 14 (5-7) ◽

pp. 531-544 ◽

Cited By ~ 20

Author(s):

S. Jay Smith ◽

Samue L. P. Caudill ◽

Karen K. Steinberg ◽

Stephen B. Thacker

Keyword(s):

Dose Response ◽

Meta Analysis ◽

Epidemiological Studies ◽

Response Data

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Dairy consumption and CVD: a systematic review and meta-analysis

British Journal Of Nutrition ◽

10.1017/s0007114515005000 ◽

2016 ◽

Vol 115 (4) ◽

pp. 737-750 ◽

Cited By ~ 120

Author(s):

Dominik D. Alexander ◽

Lauren C. Bylsma ◽

Ashley J. Vargas ◽

Sarah S. Cohen ◽

Abigail Doucette ◽

...

Keyword(s):

Cohort Studies ◽

Dose Response ◽

Prospective Cohort ◽

Meta Analysis ◽

Epidemiological Studies ◽

Sensitivity Analyses ◽

Dairy Intake ◽

Prospective Cohort Studies ◽

Dairy Consumption ◽

Risk Estimates

AbstractInverse associations between dairy consumption and CVD have been reported in several epidemiological studies. Our objective was to conduct a meta-analysis of prospective cohort studies of dairy intake and CVD. A comprehensive literature search was conducted to identify studies that reported risk estimates for total dairy intake, individual dairy products, low/full-fat dairy intake, Ca from dairy sources and CVD, CHD and stroke. Random-effects meta-analyses were used to generate summary relative risk estimates (SRRE) for high v. low intake and stratified intake dose–response analyses. Additional dose–response analyses were performed. Heterogeneity was examined in sub-group and sensitivity analyses. In total, thirty-one unique cohort studies were identified and included in the meta-analysis. Several statistically significant SRRE below 1.0 were observed, namely for total dairy intake and stroke (SRRE=0·91; 95 % CI 0·83, 0·99), cheese intake and CHD (SRRE=0·82; 95 % CI 0·72, 0·93) and stroke (SRRE=0·87; 95 % CI 0·77, 0·99), and Ca from dairy sources and stroke (SRRE=0·69; 95 % CI 0·60, 0·81). However, there was little evidence for inverse dose–response relationships between the dairy variables and CHD and stroke after adjusting for within-study covariance. The results of this meta-analysis of prospective cohort studies have shown that dairy consumption may be associated with reduced risks of CVD, although additional data are needed to more comprehensively examine potential dose–response patterns.

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