Reply to: “Talking about mediation in health and physical activity sciences

Francesco Zaccardi (285809)

Mark Hamer (1254141)

Panayotes Demakakos (196562)

Thomas E. Yates (7237088)

Atherosclerosis

Hamer, M

Yates, T

Zaccardi, F

Demakakos, P

UCL Discovery

1  Response: Talking about mediation  Mark Hamer,1,2,3 PhD, Thomas Yates,3,4 PhD, Francesco Zaccardi,3,4 MD, Panayotes Demakakos,2 PhD  1School Sport, Exercise & Health Sciences, National Centre for Sport and Exercise Medicine - East Midlands, Loughborough University, Loughborough LE11 3TU, United Kingdom. 2Department of Epidemiology and Public Health, University College London, London. 3 NIHR Leicester Biomedical Research Centre 4University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital  Correspondence: Prof Mark Hamer, National Centre for Sport and Exercise Medicine - East Midlands, Loughborough University, Loughborough LE11 3TU, United Kingdom. Email: m.hamer@lboro.ac.uk      Word count = 384          2  To The Editor Werneck1 reflects on the definition of “mediation” in relation to our recently published findings on TV viewing, inflammatory markers and mortality.2   In epidemiological research, the interpretation of mediation should be based both on conceptual and empirical grounds. Our study was built on a strong conceptual framework as there is good evidence from both observational3 and experimental4 work to suggest sedentary behaviours may cause inflammatory responses; in addition, inflammatory processes have been mechanistically implicated in atherosclerosis and the ageing cardiovascular system.5 In our paper we demonstrated that inflammatory markers were indeed independently associated with mortality in fully adjusted models.  We also confirm the other precondition to mediation was met with TV viewing being associated with CRP and fibrinogen after adjustment for variables reported in Model 2 (age, sex, physical activity, smoking, alcohol intake, depressive symptoms, long standing illness, disability).3 Thus, the consistently replicated association between TV viewing and mortality6 may be plausibly explained (mediated), in part, through inflammatory markers. Over and above the analyses presented in our paper, Werneck suggests it is highly recommended to test the indirect effect, which could be made through Sobel test or resampling methods. These methods, however, were primarily designed to be conducted on continuous data and not time to event analyses. To our knowledge, robust approaches to mediation analysis with continuous mediators and survival outcomes are still under methodological development and lack available coding in common statistical packages. Under these circumstances, making inferences about the degree of mediation from the attenuation of Hazard Ratios when adding the possible mediator into the survival model 3  remains a common approach in epidemiology, including in large international collaborations.7 The issue of possible interaction between mediators is raised. We decided to separately model groups of mediators (ie, inflammatory, metabolic) that shared common mechanistic pathways so as to counteract possible interactions between them inside the models. However, there is less reason to suspect an interaction between variables within the same category. This was demonstrated in subsequent analyses where we modelled each mediator separately (Table 1); results or interpretation are not appreciably changed to those reported in the paper. In summary, we agree it is important to undertake robust approaches to test mediation, although interpretation should not only be based on empirical grounds, but also in combination with a strong underlying conceptual framework and biological plausibility.          4  References 1. Werneck A. Talking about mediation. Atherosclerosis. [In press] 2. Hamer M, Yates T, Demakakos P. Television viewing and risk of mortality: Exploring the biological plausibility, Atherosclerosis. 2017; 263: 151–155.  3. Hamer M, Smith L, Stamatakis E. Prospective association of TV viewing with acute phase reactants and coagulation markers: English Longitudinal Study of Ageing. Atherosclerosis. 2015;239(2):322-7. 4. Howard BJ, Fraser SF, Sethi P, Cerin E, Hamilton MT, Owen N, Dunstan DW, Kingwell BA. Impact on hemostatic parameters of interrupting sitting with intermittent activity. Med Sci Sports Exerc. 2013;45:1285-91. 5. Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The Aging Cardiovascular System: Understanding It at the Cellular and Clinical Levels. J Am Coll Cardiol. 2017;69(15):1952-1967. 6. Ekelund U, Steene-Johannessen J, Brown WJ, Fagerland MW, Owen N, Powell KE, Bauman A, Lee IM; Lancet Physical Activity Series 2 Executive Committe.; Lancet Sedentary Behaviour Working Group. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. Lancet. 2016;388(10051):1302-10. 7. Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G, Clays E, De Bacquer D, Van Herck K. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million participants. Lancet. 2014;383(9921):970-83.   5  Table 1. Biological mediation analyses of TV viewing and mortality (n=5,033)  Basic modela Basic + CRP Basic + Fibrinogen Basic + HbA1C Basic + HDL-C Basic + triglycerides All cause mortality (149 events)       HR per SD unitb 1.24 (1.07, 1.44) 1.20 (1.04, 1.39) 1.21 (1.04, 1.40) 1.24 (1.07, 1.44) 1.24 (1.07, 1.44) 1.24 (1.07, 1.44) In HR 0.217 0.183 0.190 0.216 0.216 0.216 CVD mortality  (29 events)       HR per SD unitb 1.50 (1.11, 2.03) 1.44 (1.06, 1.95) 1.45 (1.07, 1.97) 1.51 (1.11, 2.05) 1.49 (1.10, 2.02) 1.49 (1.10, 2.03) In HR 0.404 0.361 0.374 0.411 0.398 0.400 aadjusted for age, sex, physical activity, smoking, alcohol intake, depressive symptoms, long standing illness, disability (ADLs/IADLs), body mass index, systolic blood pressure. bHazard ratio (HR) for TV viewing modelled continuously per SD increase (4.2 hrs/d)6  Conflict of interest None of the authors report any conflicts of interest.  Acknowledgements Hamer and Yates acknowledge support from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, which is a partnership between University Hospitals of Leicester NHS Trust, Loughborough University and the University of Leicester. 

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