DOES was designed as a population-based longitudinal research project. The setting was Dubbo, a semi-rural city in Dubbo which is about 350 km from Sydney. Dubbo is a very nice little city with a close knit community. Approximately 4000 individuals in Dubbo have been recruited to the study. The initial recruitment criterion was being aged 60 years or older in 1989 and included both men and women. There were otherwise no inclusion or exclusion criteria. Individuals return every two-three years for repeat measurements and sample collection. For some individuals there have been 10 return visits and individuals have been followed for up to 28 years. Until now, DOES is probably the longest running study of osteoporosis in men and women worldwide.
The study includes a number of large, extended families, and large numbers of individuals of advanced age – for example more than 1500 participants are over 85 years of age and 99 individuals over 100 years of age. DOES has become a resource for genomic research, not only in the musculoskeletal field, but also in other chronic conditions.
Extensive data pertaining to clinical history and environmental factors have been collected over the years. Indeed, DOES has accumulated a wealth of data unmatched by any other large-scale population based studies in the field. Throughout the study, bone mineral density, body composition parameters (lean mass and fat mass) have been measured, a detailed clinical history and measurements taken, whole blood collected for DNA isolation and serum collected for biochemical studies. Ethical authority and informed consent have been obtained for future genomic studies.
DOES has made already made seminal contributions to the osteoporosis field, including the first studies of the genetics of osteoporosis, the discovery of genes associated with bone density, the discovery that men also develop osteoporosis and that osteoporosis is associated with premature mortality. The data from DOES was the basis for the development of the Garvan Fracture Risk Calculator, arguably the most robust predictive tool available globally. Critically, the risk tool is now being translated into tools for general practitioners and consumers as BoneTracker.
The study has resulted in more than 145 publications, in high impact journals including, Lancet, BMJ, Nature, Nature Genetic and JAMA and the premier journals in the field, Journal of Bone and Mineral Research and Clinical Endocrinology and Metabolism. These have been cited more than 11,000 times with 45 papers having been cited >100 times, including 2 papers with more than 1000 citations. Two papers were classified as “highly cited” work by ISI. DOES has also been the catalyst for an international consortium, led by Garvan, with more than 10 million people, to evaluate the effect of fractures and their treatment on mortality. Importantly, the current WHO definition for osteoporosis as a T-score of -2.5, i.e. 2.5 or more standard deviations below young normal values, was based in large part on initial work from DOES. Some selected recent findings can be highlighted as follows:
- Risk of subsequent fracture following a prior fracture. As noted above, analysis of 905 women and 337 men with an initial fracture showed a similar increased absolute risk of subsequent fracture in both women and men following virtually all low-trauma fractures except ankle fractures in women and rib fractures in men. For both sexes, absolute subsequent fracture risk was equal to or greater than the risk of an initial fracture for a woman 10 years older or for a man 20 years older. The increased risk persisted for up to 10 years depending on age and sex, with about 50% of surviving men and women having another fracture.
- Risk of mortality following a fracture. In a study of association between fracture, re-fracture and mortality, it was shown that the risk of mortality increased 2 to 3-fold among both men and women with a fracture , albeit somewhat greater in men . Interestingly, excessive weight loss and weight fluctuation (measured by the within-subject coefficient of variation) were independent predictors of mortality risk in both sexes but again more marked in men.
- Quality of life after fracture. Longitudinal analysis of SF-36 data indicated that physical status among individuals who had sustained a fracture deteriorated more than among those without a fracture, and this effect was apparent even after excluding hip fracture. The deterioration was more obvious during the first 3 months post-fracture, but did not return to baseline by 12 months. The deterioration in quality of life observed among fracture subjects at 12 months was comparable to the reduction seen in patients with myocardial infarction and stroke.
- Development of predictive models for predicting hip fracture risk in an individual. Using longitudinal data from DOES, we have developed a nomogram-based model, including factors such as femoral neck BMD, prior fracture and history of falls, for predicting the 5-year and 10-year risks of hip fracture for any elderly man and woman. The model performed better than any previous models with an ROC of 0.85 for both sexes.
To capitalize on potential opportunities requires a change in thinking and to create a new vehicle to take this forward. This could involve establishing a new entity for the Study. Such a vehicle would introduce new activities and support broader questions brought forward by others under the umbrella organization of the current activities. This could involve sequencing individuals in the DOES cohort for genomic studies and making the data available to the wider research community; recruiting new cohorts to address new high impact questions; expanding the current clinical focus from osteoporosis to other disease areas, including metabolic disorders; and establishing a bio-repository for both data and materials generated from the DOES cohort and new cohorts for interrogation by the wider scientific community. From my point of view, the Dubbo study is a great resource for multidisciplinary research into healthy ageing. So, if you have good research idea (any idea at all, clinical issues, genetics and genomics, biologic markers, ‘Big Data’ and Machine Learning, epidemiologic methods, etc) please feel free to contact me.
Some recent publications
Ho-Le TP, Center JR, Eisman JA, Nguyen HT, Nguyen TV. Prediction of Bone Mineral Density and Fragility Fracture by Genetic Profiling. J Bone Miner Res. 2017 Feb;32(2):285-293. doi: 10.1002/jbmr.2998. Epub 2016 Oct 26.
Ho-Le TP, Center JR, Eisman JA, Nguyen TV, Nguyen HT. Prediction of hip fracture in post-menopausal women using artificial neural network approach. Conf Proc IEEE Eng Med Biol Soc. 2017 Jul;2017:4207-4210.
Gourlay ML, Ritter VS, Fine JP, Overman RA, Schousboe JT, Cawthon PM, Orwoll ES, Nguyen TV, Lane NE, Cummings SR, Kado DM, Lapidus JA, Diem SJ, Ensrud KE; Osteoporotic Fractures in Men (MrOS) Study Group. Comparison of fracture risk assessment tools in older men without prior hip or spine fracture: the MrOS study. Arch Osteoporos. 2017 Oct 20;12(1):91.
Alajlouni D, Bliuc D, Tran T, Pocock N, Nguyen TV, Eisman JA, Center JR. Nonstandard Lumbar Region in Predicting Fracture Risk. J Clin Densitom. 2017 Jul 6. pii: S1094-6950(17)30026-4.
Chen W, Simpson JM, March LM, Blyth FM, Bliuc D, Tran T, Nguyen TV, Eisman JA, Center JR. Co-morbidities only account for a small proportion of excess mortality after fracture: a record linkage study of individual fracture types. J Bone Miner Res. 2018 Jan 4.
Tran T, Bliuc D, van Geel T, Adachi JD, Berger C, van den Bergh J, Eisman JA, Geusens P, Goltzman D, Hanley DA, Josse RG, Kaiser SM, Kovacs CS, Langsetmo L, Prior JC, Nguyen TV, Center JR. Population-Wide Impact of Non-Hip Non-Vertebral Fractures on Mortality. J Bone Miner Res. 2017 Sep;32(9):1802-1810.
Pham HM, Nguyen SC, Ho-Le TP, Center JR, Eisman JA, Nguyen TV. Association of Muscle Weakness With Post-Fracture Mortality in Older Men and Women: A 25-Year Prospective Study. J Bone Miner Res. 2017 Apr;32(4):698-707.
Styrkarsdottir U, Thorleifsson G, Gudjonsson SA, Sigurdsson A, Center JR, Lee SH, Nguyen TV, Kwok TC, Lee JS, Ho SC, Woo J, Leung PC, Kim BJ, Rafnar T, Kiemeney LA, Ingvarsson T, Koh JM, Tang NL, Eisman JA, Christiansen C, Sigurdsson G, Thorsteinsdottir U, Stefansson K. Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures. Nat Commun. 2016 Jan 6;7:10129.
Alarkawi D, Bliuc D, Nguyen TV, Eisman JA, Center JR. Contribution of Lumbar Spine BMD to Fracture Risk in Individuals With T-Score Discordance. J Bone Miner Res. 2016 Feb;31(2):274-80.