Cohort Profile: The Melbourne Collaborative Cohort Study (Health 2020)

The Melbourne Collaborative Cohort Study (MCCS), also known as Health 2020, was planned in the late 1980s and established in the early 1990s as an omnibus cohort to investigate prospectively the roles of diet and lifestyle in causing cancer and other non-communicable diseases.1 It was developed contemporaneously with the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2 at a time when diet and nutrition were considered important to cancer causation,3 but detailed information adequate to inform prevention was scant. The literature was dominated by inconsistent evidence generated by a large number of small case-control studies which had problems not only with statistical power and dietary assessment but also, more importantly, with forms of information bias to which such studies are prone. A prospective design was chosen to reduce these biases. We also considered that a contributing factor to the modest strengths of association between dietary factors and cancer observed by previous cohort studies, might be related to the limited range of dietary intakes within a given population. We sought ways in which we might address this and, as Melbourne had a relatively large number of migrants from Italy and Greece with distinct dietary and lifestyle differences from the majority of British descent, we deliberately targeted them for recruitment in order to broaden the range of observations of the measured lifestyle risk factors. Our original research proposal encompassed a broad range of research questions, including the full gamut of questions concerning the influence of individual foods and food groups, macronutrients and micronutrients on the risk of cancer, principally of the colorectum, breast and prostate, at least in the short term. Early questions, for example, tested the conventional wisdom regarding: the possible protective effect of fruit and vegetables and the harmful effect of red and processed meats; the effect of different dietary fats (especially oleic acid); the role of dietary fibre; and the role of alcoholic beverages. We were also interested in the role of energy balance, physical activity, overweight and obesity. To this end we took direct anthropometric and clinical measurements of all participants, including bioimpedance to estimate fat and lean mass separately, and blood pressure. Using plasma samples collected at baseline, we also had questions concerning markers of diet such as antioxidants and concentrations of circulating hormones, not only steroid homones but also peptide hormones such as insulin-like growth factor 1 (IGF-1) and their binding proteins. As we addressed these questions ourselves and contributed data to consortia to increase the range and precision of estimates, we adapted our data collection at follow-up waves to refine our approach and better answer remaining questions. We also repeated blood sampling and physical measurements to be able to address associations with changes over time. What we did not anticipate at the inception of the MCCS was the rapid growth in genomics and the value of the blood (collected to measure dietary and other markers) as a source of DNA to examine genetic risk factors and their potential interaction with lifestyle-related exposures, which has been our principal focus for the past decade or so. Between 1990 and 1994 (baseline), 41 513 residents of the Melbourne metropolitan area (24 469 women and 17 044 men), with an average age of 55 years (range 27–76; 99% aged between 40 and 69) were recruited to the study. All participants were of White European origin; most (69%) were born in Australia or New Zealand, 13% were born in Italy, 11% in Greece and 6% in the UK. The majority of participants were identified from the Victorian Electoral Enrolment Register (enrolment to vote is compulsory for all adult Australian citizens) and the Melbourne metropolitan phone directory, and were invited by letter to participate. The main recruitment clinic was organized at the premises of Cancer Council Victoria, proximal to the Melbourne central business district (CBD). Additional strategies were adopted to recruit migrants, bearing in mind that those who had not taken out Australian citizenship would not be on the electoral register: announcements were made on multicultural radio and in newspapers, clubs and churches; and a mobile recruitment unit was also driven to major Italian and Greek festivals in Melbourne and to the premises of manufacturing companies with a large number of migrant employees. Participants were invited to encourage friends and family to participate in the study. The mobile unit was also used to process Australian-born participants closer to their area of residence. The proportion of responders was not recorded for any of these recruitment strategies. Compared with the population of metropolitan Melbourne aged 40–69 years at the time of recruitment,4 MCCS participants were more likely to be older and female (59%). As expected, there was a greater proportion of Greek- and Italian-born participants and fewer Australian-born participants compared with the general populations of Victoria and Australia in the same age range (77% and 79% Australian-born, respectively).5,6 The first wave of active follow-up (follow-up 1) occurred between 1995 and 1998, approximately 4 years after recruitment for each participant. A total of 36 335 (88%) of the original participants, 21 664 women and 14 671 men, participated either by mail or phone; 778 had died before they could be contacted. A second wave of active follow-up (follow-up 2) occurred between 2003 and 2007. A total of 28 240 (68%) of the original participants, 17 138 women and 11 102 men, attended clinics organized at the Cancer Council Victoria premises near the Melbourne CBD for face-to face interviews and physical measurements; 3007 had died before they could be contacted. Those who attended this second wave were younger and more likely to be born in an English-speaking country, and had higher socioeconomic position than those who did not. No further active data collection is planned. Every year participants are sent a study newsletter, which includes a reminder to contact the study coordinator to update contact information. This has been the case since 2005; before that, newsletters were sent every 2 years. Information was collected at baseline attendance [http://www.pedigree.org.au/pedigree-studies/health2020/pages/h2020databooks.aspx] by physical measurement, interviewer-administered questionnaires on lifestyle, personal medical history and medications taken, and a self-administered food frequency questionnaire.7 Blood samples were collected from 41 133 participants; plasma (N = 40 524 participants), peripheral blood mononuclear cells (N = 9832) and buffy coats (N = 635) were separated and stored in liquid nitrogen. From the second year of recruitment, dried blood spots (N = 30 663) were stored on Guthrie card diagnostic cellulose filter paper in lieu of blood mononuclear cells or buffy coats. At follow-up 1, information on lifestyle, medical history and diet was collected by self-administered or telephone interviewer-administered questionnaire; no physical measurements or blood were taken. At follow-up 2, physical measurements were taken, interviewer- or self-administered questionnaires were used to collect lifestyle and medical history information (including medications taken) and diet was measured by self-administered food frequency questionnaire. Blood was collected from 26 824 follow-up 2 participants (99%) and stored on Guthrie cards for 26 522. Plasma (N = 26 318), serum (N = 26 606) and buffy coats (N = 26 299) were aliquoted and stored in liquid nitrogen. Formalin-fixed paraffin-embedded tissue has been collected from 3070 tumours diagnosed in cohort participants, the vast majority being breast, colorectal and prostate cancers. Further details of the samples and information collected are provided in Table 1. Data and samples collected at baseline and follow-up for participants in the Melbourne Collaborative Cohort Study aDeciles of the Index of Relative Socioeconomic Disadvantage (IRSD) based on the smallest geographical area of output (average population of 400 persons) defined by the population census, to which each participant’s usual residential address at baseline and follow-up 2 have been mapped. bAt baseline, type of cancer was not specified and only first-degree relatives were considered; similar information was collected at follow-up 1, but with type of cancer specified; at follow-up 2, first-degree family histories of colorectal, breast and prostate cancer, as well as heart attack and stroke, were reported. cWeight change, asthma, angina, hypertension, diabetes, arthritis, cancer, kidney stones, gallstones, heart attack, stroke. dBy drug name; aspirin, NSAIDS, paracetamol collected specifically at follow-up 1. eQuestions about feelings at baseline and follow-up 1; psychological distress or anxiety (Kessler 10), social support, quality of life (SF12) and ability to perform activities of daily living assessed at follow-up 2. fCollected via a food frequency questionnaire developed specifically for this study.2 gHeight and bioimpedance (to determine lean and fat mass) were collected at baseline only; weight, waist circumference and hip circumference were collected at baseline and follow-up 2; weight and waist circumference were self-reported at follow-up 1; photocopies of hands were taken at follow-up 2, to measure the ratio of second to fourth digit length. hFormalin-fixed paraffin-embedded samples have been collected for incident cases of colorectal (N = 869), prostate (N = 1074), breast (N = 1005), kidney (N = 206) and endometrial cancer (N = 136). iMeasured in plasma for the main case-cohort sub-study (see description in Sub-studies). jMeasured from dried blood spots for participants (N = 7045) selected for purpose-designed case-cohort sub-study (based on only participants with dried blood spot samples). kMeasured in plasma for selected nested case-control studies (lung, urothelial cell carcinoma, kidney). lMeaured in plasma at baseline and serum at follow-up 2 as part of the HealthIron sub-study (see description in Sub-studies). mTaken as part of the CERA sub-study (see description in Sub-studies). nSee description in Genetic data. oSee description in Epigenetic data. Data and samples collected at baseline and follow-up for participants in the Melbourne Collaborative Cohort Study aDeciles of the Index of Relative Socioeconomic Disadvantage (IRSD) based on the smallest geographical area of output (average population of 400 persons) defined by the population census, to which each participant’s usual residential address at baseline and follow-up 2 have been mapped. bAt baseline, type of cancer was not specified and only first-degree relatives were considered; similar information was collected at follow-up 1, but with type of cancer specified; at follow-up 2, first-degree family histories of colorectal, breast and prostate cancer, as well as heart attack and stroke, were reported. cWeight change, asthma, angina, hypertension, diabetes, arthritis, cancer, kidney stones, gallstones, heart attack, stroke. dBy drug name; aspirin, NSAIDS, paracetamol collected specifically at follow-up 1. eQuestions about feelings at baseline and follow-up 1; psychological distress or anxiety (Kessler 10), social support, quality of life (SF12) and ability to perform activities of daily living assessed at follow-up 2. fCollected via a food frequency questionnaire developed specifically for this study.2 gHeight and bioimpedance (to determine lean and fat mass) were collected at baseline only; weight, waist circumference and hip circumference were collected at baseline and follow-up 2; weight and waist circumference were self-reported at follow-up 1; photocopies of hands were taken at follow-up 2, to measure the ratio of second to fourth digit length. hFormalin-fixed paraffin-embedded samples have been collected for incident cases of colorectal (N = 869), prostate (N = 1074), breast (N = 1005), kidney (N = 206) and endometrial cancer (N = 136). iMeasured in plasma for the main case-cohort sub-study (see description in Sub-studies). jMeasured from dried blood spots for participants (N = 7045) selected for purpose-designed case-cohort sub-study (based on only participants with dried blood spot samples). kMeasured in plasma for selected nested case-control studies (lung, urothelial cell carcinoma, kidney). lMeaured in plasma at baseline and serum at follow-up 2 as part of the HealthIron sub-study (see description in Sub-studies). mTaken as part of the CERA sub-study (see description in Sub-studies). nSee description in Genetic data. oSee description in Epigenetic data. A food frequency questionnaire was developed specifically to measure usual dietary intakes by cohort participants, with the food list based on weighed food records completed by a group of 810 men and women representing the main country of birth groups within the MCCS.7 The most recent version of the dietary questionnaire (DQES v3.2)8 [http://www.cancervic.org.au/research/epidemiology/nutritional_assessment_services] is available for use on a fee-for-service basis. It estimates nutritional intake based on 144 foods and beverages grouped as grain-based foods, dairy foods and fats, meat, fish and seafood, fruit, vegetables, miscellaneous, tea/coffee and alcoholic beverages in electronic (online) format that can be self- or interviewer-administered. Participant addresses are updated using information from the Victorian Electoral Enrolment Register, which is received every 6 months. Incident diagnosis of cancer and deaths are identified by at least annual record linkage to the Victorian Cancer Registry (VCR) and the Victorian Registry of Births, Deaths and Marriages. Both registries are considered complete, with notification to the VCR of all cancers diagnosed in Victoria mandated by legislation since 1981. To capture these events for participants who may have moved interstate, these Victorian linkages are complemented by at least 2-yearly record linkage to the National Death Index (NDI) and the Australian Cancer Database, compiled by the Australian Institute of Health and Welfare (to which all state and territory cancer and death registries in Australia contribute). Linked NDI data also include cause of death. Altogether, 11 222 incident cancers (1553 breast; 1262 colorectal; 1975 prostate; 761 lung) were diagnosed in MCCS participants to June 2015 and 10 304 participants had died by December 2015. A case-cohort sub-study was defined9 in 2003 to provide a more economical design within which to perform expensive assays to measure various molecules in the stored plasma and to analyse their associations with selected diseases. The sub-study includes all incident cases to 30 June 2002 of prostate cancer (n = 605), breast cancer (n = 576), colorectal cancer (n = 525), type 2 diabetes (n = 402)10 and cardiovascular death (n = 532), and a random sample of all MCCS participants, making a total of 6950 MCCS participants. Plasma-based assays included biomarkers of dietary intake (antioxidants11,12 and fatty acids10,13–16), steroid sex hormones,17,18 homocysteine, insulin, triglycerides, high-density lipoprotein (HDL) cholesterol, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3),19,20 nuclear magnetic resonance (NMR)-determined lipoprotein subclass levels21 and C-reactive protein (CRP). At follow-up 2, non-mydriatic retinal photography was performed by collaborators from the Centre for Eye Research Australia (CERA) in order to study age-related macular degeneration (AMD) and early markers of cardiovascular disease (CVD). A total of 22 405 follow-up 2 participants (80%) took part in this study, with digital retina images from 21 287 passing quality control.22 HealthIron, a study of hereditary haemochromatosis, was designed to genotype 31 192 participants of northern European descent and subsequently to assess clinically a random sample of 1438 participants stratified according to high-iron Fe (HFE) genotypes C282Y and H63D. There were 203 C282Y homozygotes.23 The strengths of this study were its size and the availability of stored plasma from baseline attendance, which permitted repeated measures of iron indices 12 years apart.24,25 In 2009, record linkage was performed between the MCCS and BreastScreen Victoria, which is part of Australia’s national breast cancer BreastScreen was established in to targeted at women aged years. the 469 women in the had attended BreastScreen Victoria at least and, from a nested case-control study was designed including incident breast cancer cases diagnosed before each to women selected in this case-control study, had had a between baseline and age at diagnosis of the case in each case-control and for each of the to baseline was from the total breast area and area were using has been on DNA samples from a of MCCS participants using the include and incident cases of breast (N = prostate (N = and colorectal cancer (N = and incident cases of urothelial cell (N = as well as to a of these using includes more than genetic including a and using to the has generated genotypes for DNA has been using the in peripheral blood DNA samples collected at baseline from participants in nested case-control include breast prostate cancer, colorectal cancer, urothelial cell kidney cancer, cancer, and 469 case-control All cases were at genotype data are available for all participants in the first of these has also been measured in DNA from peripheral blood samples collected at follow-up 2 for a of from these studies that we have repeated on average 10 years for participants. MCCS are at the MCCS was being was that diet an important role in cancer In the Cancer Research that there was evidence that of fruit and vegetables the risk of on the of data from case-control years the updated no evidence for an association between intake of fruit and vegetables with cancer at any based on more recent prospective In the was updated with the evidence available only associations between of fruit and vegetables and cancer The MCCS not to these The MCCS has been used to investigate associations between diet and a range of using a and a Index and have been in to type 2 urothelial and breast psychological and all the of based on vegetables and limited and other dietary may a role in as they are in which is for DNA DNA and of The MCCS has been used to assess associations between intakes of these and risk of and cancer and urothelial cell The have been inconsistent and not intakes of these as a of cancer associations between fatty and have been using dietary intake and data. and colorectal in and with risk factor for and there is evidence that fatty fish and are to and made from In the MCCS identified the of measures of size to cancer the of association by cancer was also related to and more physical activity, a diet in and and relatively in fat and and limited were with weight after weight after age was with direct measurements of waist and hip was a of this as these measures are available in large cohort Relative of cancer with waist The in to information on of alcoholic beverages at baseline and also collected data on data have been used to assess the of cancers and 2 as well as Relative of cancer with The most have from data with other in the that overweight and are with and the of genetic with risk of breast and prostate The MCCS with other and research consortia in cancer and include the National Cancer Institute Cohort the of Prospective of and Cancer and the Cohort the on its in the and Cancer Cohort the Cancer and the Cancer to Cancer in the the MCCS has contributed to the of the vast majority of the genetic for each of and prostate of and have that to these established genetic risk factors with each and with other potential and established risk to influence cancer MCCS in with the Cancer and Cancer Cohort has contributed to the of for these The main strengths of the MCCS include its its blood and direct physical measurements and questionnaires to capture lifestyle The of European migrants also the range of social and lifestyle follow-up since recruitment and to follow-up participants are known to have the MCCS a for the prospective of the role of other lifestyle and in the of over 41 participants, the MCCS has adequate power to research over a of and but has limited power for and To increase available power to address these the MCCS has contributed to consortia and has in this for example, further the to study the dietary and genetic of The MCCS has data at time and direct physical measurements and blood samples collected at time DNA has also been for most of the cohort for genetic with and blood DNA for a It also has and follow-up for cancer death and cause of death. interested in using the MCCS can contact the by at The MCCS has a process for to its data and for research the proposal has been by an an of can be for by the MCCS a data can be for Data and are sent to collaborators by with on a basis. The is to annual for the of the The MCCS also has to that all collaborators are given the to as or are are at The MCCS is an omnibus cohort to investigate prospectively the roles of diet and lifestyle in causing cancer and other non-communicable diseases. Between 1990 and 1994 (baseline), 41 513 residents of the Melbourne metropolitan area with an average age of 55 years (range 27–76; 99% aged between 40 and 69) were has included waves of data in and linkage to the and national cancer and death registries is for all living participants. The a range of and lifestyle including anthropometric and clinical blood genetic and biomarkers and to the MCCS data and for research Cohort recruitment was by Cancer Council Victoria and The MCCS was further by and from the Australian National Health and Research Council and follow-up and data has been by Cancer Council Victoria since Research related to was by the Victorian Cancer Research The MCCS was made possible by the of including the original the that recruited the participants and on and the of Melbourne residents who to participate in the study. of