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1.  Meat consumption and risk of primary hip and knee joint replacement due to osteoarthritis: a prospective cohort study 
There is emerging evidence for a beneficial effect of meat consumption on the musculoskeletal system. However, whether it affects the risk of knee and hip osteoarthritis is unknown. We performed a prospective cohort study to examine the relationship between meat consumption and risk of primary hip and knee replacement for osteoarthritis.
Eligible 35,331 participants were selected from the Melbourne Collaborative Cohort Study recruited during 1990-1994. Consumption of fresh red meat, processed meat, chicken, and fish was assessed using a food frequency questionnaire. Primary hip and knee replacement for osteoarthritis during 2001-2005 was determined by linking the cohort records to the Australian National Joint Replacement Registry.
There was a negative dose-response relationship between fresh red meat consumption and the risk of hip replacement (hazard ratio (HR) 0.94 per increase in intake of one time/week, 95% confidence interval (CI) 0.89-0.98). In contrast, there was no association with knee replacement risk (HR 0.98, 95% CI 0.94-1.02). Consumption of processed meat, chicken and fish were not associated with risk of hip or knee replacement.
A high level consumption of fresh red meat was associated with a decreased risk of hip, but not knee, joint replacement for osteoarthritis. One possible mechanism to explain these differential associations may be via an effect of meat intake on bone strength and hip shape. Further confirmatory studies are warranted.
PMCID: PMC3025929  PMID: 21235820
2.  Reduced rates of primary joint replacement for osteoarthritis in Italian and Greek migrants to Australia: the Melbourne Collaborative Cohort Study 
Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals.
Eligible participants (n = 39,023) aged 27 to 75 years, born in Italy, Greece, Australia and the United Kingdom, were recruited for the Melbourne Collaborative Cohort Study between 1990 and 1994. Primary hip and knee replacement for osteoarthritis between 2001 and 2005 was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry.
Participants born in Italy and Greece had a lower rate of primary joint replacement compared with those born in Australia (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.26 to 0.39, P < 0.001), independent of age, gender, body mass index, education level, and physical functioning. This lower rate was observed for joint replacements performed in private hospitals (HR 0.17, 95% CI 0.13 to 0.23), but not for joint replacements performed in public hospitals (HR 0.96, 95% CI 0.72 to 1.29).
People born in Italy and Greece had a lower rate of primary joint replacement for osteoarthritis in this cohort study compared with Australian-born people, which could not simply be explained by factors such as education level, physical functioning, and weight. Although differential access to health care found in the population may explain the different rates of joint replacement, it may be that social factors and preferences regarding treatment or different rates of progression to end-stage osteoarthritis in this population are important to ethnic disparity.
PMCID: PMC2714137  PMID: 19505315
3.  The association of anthropometric measures and osteoarthritis knee in non‐obese subjects: a cross sectional study 
Clinics  2011;66(2):275-279.
Body mass index (BMI) and knee osteoarthritis have a strong association, but other anthropometric measures lack such associations. To date, no study has evaluated non‐obese knee osteoarthritis to negate the systemic and metabolic effects of obesity. This study examines the validity of the contention that BMI and other anthropometric measures have a significant relationship with knee osteoarthritis.
In total, 180 subjects with a diagnosis of knee osteoarthritis were recruited and classified according to Kellgren‐Lawrence (KL) grades. Body mass index, mid‐upper arm circumference, waist‐hip ratio and triceps‐skinfold thickness were recorded by standard procedures. Osteoarthritis outcome scores (WOMAC) were evaluated.
(1) In both genders, the BMI was significantly higher for KL grade 4 than for grade 2; triceps‐skinfold thickness was positively correlated with the joint space width of the tibial medial compartment. (2) In males, triceps‐skinfold thickness significantly increased as the KL grades moved from 2 to 4; the significantly higher BMI found in varus aligned knees was positively correlated with WOMAC scores. (3) In females, the waist‐hip ratio was significantly higher for KL grade 4 than for grade 2; a significant correlation was found between BMI and WOMAC scores. The waist‐hip ratio was significantly associated with varus aligned knees and it positively correlated with WOMAC scores and with the joint space width of the tibial medial compartment. The mid‐upper arm circumference demonstrated no correlation with knee osteoarthritis.
This study validates the contention that BMI and other anthropometric measures have a significant association with knee osteoarthritis. Contrary to common belief, the triceps‐skinfold thickness (peripheral fat) in males and the waist‐hip ratio (central fat) in females were more strongly associated with knee osteoarthritis than BMI.
PMCID: PMC3059862  PMID: 21484046
Osteoarthritis; Knee; Obesity; Anthropometric measures; BMI
4.  Revision Rates after Primary Hip and Knee Replacement in England between 2003 and 2006 
PLoS Medicine  2008;5(9):e179.
Hip and knee replacement are some of the most frequently performed surgical procedures in the world. Resurfacing of the hip and unicondylar knee replacement are increasingly being used. There is relatively little evidence on their performance. To study performance of joint replacement in England, we investigated revision rates in the first 3 y after hip or knee replacement according to prosthesis type.
Methods and Findings
We linked records of the National Joint Registry for England and Wales and the Hospital Episode Statistics for patients with a primary hip or knee replacement in the National Health Service in England between April 2003 and September 2006. Hospital Episode Statistics records of succeeding admissions were used to identify revisions for any reason. 76,576 patients with a primary hip replacement and 80,697 with a primary knee replacement were included (51% of all primary hip and knee replacements done in the English National Health Service). In hip patients, 3-y revision rates were 0.9% (95% confidence interval [CI] 0.8%–1.1%) with cemented, 2.0% (1.7%–2.3%) with cementless, 1.5% (1.1%–2.0% CI) with “hybrid” prostheses, and 2.6% (2.1%–3.1%) with hip resurfacing (p < 0.0001). Revision rates after hip resurfacing were increased especially in women. In knee patients, 3-y revision rates were 1.4% (1.2%–1.5% CI) with cemented, 1.5% (1.1%–2.1% CI) with cementless, and 2.8% (1.8%–4.5% CI) with unicondylar prostheses (p < 0.0001). Revision rates after knee replacement strongly decreased with age.
Overall, about one in 75 patients needed a revision of their prosthesis within 3 y. On the basis of our data, consideration should be given to using hip resurfacing only in male patients and unicondylar knee replacement only in elderly patients.
Jan van der Meulen and colleagues show that about one in 75 patients with a primary hip or knee replacement needed a revision of their prosthesis within 3 years.
Editors' Summary
Though records show attempts to replace a hip date back to 1891, it was not till the 1960s before total hip replacements were successfully performed, and the 1970s before total knee replacements were carried out. These procedures are some of the most frequently performed surgical operations, with a total of 160,00 total hip and knee replacement procedures carried out in England and Wales and about half a million in the US in 2006. Hip and knee replacements are most commonly used as a treatment for severe arthritis once other approaches, such as pain relief medications, have failed. A total hip replacement involves replacing the head of the femur (the thigh bone) with an artificial component, typically metal; the socket into which the new femur head will insert is also replaced with artificial components. In an alternative procedure, resurfacing, rather than replacing the entire joint, the diseased surfaces are replaced with metal components. This procedure may be better suited to patients with less severe disease, and is also thought to result in quicker recovery. The techniques for hip and knee replacement can also be divided into those where a cement is used to position the metal implant into the bone (cemented) versus those where cement is not used (cementless).
Why Was This Study Done?
To date, little evidence has been available to compare patient outcomes following hip or knee replacement with the many different types of techniques and prostheses available. National registries have been established in a number of countries to try to collect data in order to build the evidence base for evaluating different types of prosthesis. Specifically, it is important to find out if there are any important differences in revision rates (how often the hip replacement has to be re-done) following surgery using the different techniques. In England and Wales, the National Joint Registry (NJR) has collected data on patient characteristics, types of prostheses implanted, and the type of surgical procedures used, since its initiation in April 2003.
What Did the Researchers Do and Find?
The researchers linked the records of the NJR and the Hospital Episode Statistics (HES) for patients treated by the NHS in England who had undergone a primary hip and knee replacement between April 2003 and September 2006. The HES database contains records of all admissions to NHS hospitals in England, and allowed the researchers to more accurately identify revisions of procedures that were done on patients in the NJR database.
They identified 327,557 primary hip or knee replacement procedures performed during that time period, but only 167,076 could be linked between the two databases.
76,576 patients in the linked database had undergone a primary hip replacement. The overall revision rate was 1.4% (95% confidence interval [CI] 1.2%–1.5%) at 3 years, with the lowest revision rates experienced by patients who had cemented prostheses. Women were found to have higher revision rates after hip resurfacing, and the revision rate was about twice as high in patients who had had a hip replacement for other indications than osteoarthritis. A patient's age did not appear to affect revision rates after hip surgery.
80,697 patients in the linked database had undergone a primary knee replacement. The overall revision rate was 1.4% (95% CI 1.3%–1.6%) at three years, again with the lowest rates of replacement experienced by patients who had cemented prostheses. Revision rates after knee replacement strongly decreased with age.
What Do These Findings Mean?
Overall, about one in 75 patients required a revision of their joint replacement, which is considered low, and cemented hip or knee prosthesis had the lowest revision rates. Post hip replacement, the highest revision rate was in patients who had undergone hip resurfacing, especially women. Following knee replacement, the highest revision rate was in patients who had undergone unicondylar prosthesis. However, in this study patients were only followed up for three years after the initial knee replacement, and it's possible that different patterns regarding the success of these differing techniques may emerge after longer follow-up. Importantly, this study was entirely observational, and data were collected from patients who had been managed according to routine clinical practice (rather than being randomly assigned to different procedures). Substantial differences in the age and clinical characteristics of patients receiving the different procedures were seen. As a result, it's not possible to directly draw conclusions on the relative benefits or harms of the different procedures, but this study provides important benchmark data with which to evaluate future performance of different procedures and types of implant.
Additional Information.
Please access these Web sites via the online version of this summary at
The website of the British Orthopaedic Association contains information for patients and surgeons
The website of the National Institute for Health and Clinical Excellence contains guidance on hip prostheses
Information is available from the US National Institutes of Health (Medline) on hip replacement, including interactive tutorials and information about rehabilitation and recovery
Medline also provides similar resources for knee replacement
The NHS provides information for patients on hip and knee replacement, including questions patients might ask, real stories, and useful links
The National Joint Registry provides general information about joint replacement, as well as allowing users to download statistics on the data it has collected on the numbers of procedures carried out in the UK
PMCID: PMC2528048  PMID: 18767900
5.  Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies 
Lancet  2011;377(9784):1085-1095.
Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.
We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4·56 kg/m2 higher BMI, 12·6 cm higher waist circumference, and 0·083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.
Individual records were available for 221 934 people in 17 countries (14 297 incident cardiovascular disease outcomes; 1·87 million person-years at risk). Serial adiposity assessments were made in up to 63 821 people (mean interval 5·7 years [SD 3·9]). In people with BMI of 20 kg/m2 or higher, HRs for cardiovascular disease were 1·23 (95% CI 1·17–1·29) with BMI, 1·27 (1·20–1·33) with waist circumference, and 1·25 (1·19–1·31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1·07 (1·03–1·11) with BMI, 1·10 (1·05–1·14) with waist circumference, and 1·12 (1·08–1·15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of −0·0001, −0·0001, and 0·0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement −0·19%, −0·05%, and −0·05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0·95, 95% CI 0·93–0·97) than for waist circumference (0·86, 0·83–0·89) or waist-to-hip ratio (0·63, 0·57–0·70).
BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.
British Heart Foundation and UK Medical Research Council.
PMCID: PMC3145074  PMID: 21397319
6.  Central adiposity, regional fat distribution, and the risk of cholecystectomy in women 
Gut  2006;55(5):708-714.
Whether central adiposity contributes independently of total adiposity to the risk for gall stones is inconclusive. We examined prospectively indicators of central adiposity in relation to the occurrence of gall stone disease.
We evaluated the relationship between abdominal circumference and waist to hip ratio and risk of cholecystectomy in a cohort of women who had no history of gall stone disease. As part of the Nurses' Health Study, the women reported on questionnaires their weights, heights, and waist and hip circumferences, and the occurrence of cholecystectomy. A total of 42 312 women, aged 39–66 years in 1986, who were free of prior gall stone disease, provided complete waist and hip circumference measurements in 1986.
We documented 3197 cases of cholecystectomy during 514 283 person years of follow up. After adjusting simultaneously for regional (waist circumference or waist to hip ratio) and total adiposity (body mass index) measures as well as for other risk factors of gall stone disease, women with a height adjusted waist circumference of 36 inches or larger had a relative risk (RR) of 1.96 (95% confidence interval (CI) 1.53–2.51; p trend <0.0001) compared with women with a height adjusted waist circumference of less than 26 inches. Waist to hip ratio was directly associated with the risk, with an RR of 1.39 (95% CI 1.16–1.66; p trend <0.0001) for women with a waist to hip ratio of 0.86 or higher compared with women with a waist to hip ratio of less than 0.70.
Abdominal circumference and waist to hip ratio were associated with an increased risk of cholecystectomy, independently of body mass index in women.
PMCID: PMC1856127  PMID: 16478796
central obesity; gall bladder; cholecystectomy; gall stone; women
7.  What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients 
BMJ Open  2012;2(1):e000435.
Total hip or knee replacement is highly successful when judged by prosthesis-related outcomes. However, some people experience long-term pain.
To review published studies in representative populations with total hip or knee replacement for the treatment of osteoarthritis reporting proportions of people by pain intensity.
Data sources
MEDLINE and EMBASE databases searched to January 2011 with no language restrictions. Citations of key articles in ISI Web of Science and reference lists were checked.
Study eligibility criteria, participants and interventions
Prospective studies of consecutive, unselected osteoarthritis patients representative of the primary total hip or knee replacement population, with intensities of patient-centred pain measured after 3 months to 5-year follow-up.
Study appraisal and synthesis methods
Two authors screened titles and abstracts. Data extracted by one author were checked independently against original articles by a second. For each study, the authors summarised the proportions of people with different severities of pain in the operated joint.
Searches identified 1308 articles of which 115 reported patient-centred pain outcomes. Fourteen articles describing 17 cohorts (6 with hip and 11 with knee replacement) presented appropriate data on pain intensity. The proportion of people with an unfavourable long-term pain outcome in studies ranged from about 7% to 23% after hip and 10% to 34% after knee replacement. In the best quality studies, an unfavourable pain outcome was reported in 9% or more of patients after hip and about 20% of patients after knee replacement.
Other studies reported mean values of pain outcomes. These and routine clinical studies are potential sources of relevant data.
Conclusions and implications of key findings
After hip and knee replacement, a significant proportion of people have painful joints. There is an urgent need to improve general awareness of this possibility and to address determinants of good and bad outcomes.
Article summary
Article focus
Total hip and knee replacement have good clinical outcomes.
There is a perception that some people experience long-term pain after their joint replacement.
We aim to establish the proportion of patients experiencing long-term pain after joint replacement.
Key messages
Well-conducted studies in representative populations of patients with total hip and knee joint replacement suggest that a significant proportion of people continue to have painful joints after surgery.
The proportion of people with an unfavourable long-term pain outcome in studies ranged from about 7% to 23% after hip and 10% to 34% after knee replacement. In the best quality studies, an unfavourable pain outcome was reported in 9% or more of patients after total hip and about 20% of patients after total knee replacement.
There is an urgent need to improve general awareness that some patients experience long-term pain after joint replacement and to address the determinants of good and bad outcomes.
Strengths and limitations of this study
Systematic review conducted according to established methods and guidelines identified 17 studies in representative populations of patients with total hip or knee replacement.
Pain outcome data are widely recorded as mean values but only a minority of studies reported outcomes as proportions with pain at follow-up.
The small number of studies and different pain outcome measures precluded meta-analysis, calculation of a summary estimate and exploration of sources of heterogeneity.
PMCID: PMC3289991  PMID: 22357571
8.  Factors associated with change in pain and disability over time: a community-based prospective observational study of hip and knee osteoarthritis 
Hip and knee osteoarthritis are frequent causes of primary care consultations. They are considered slowly progressive disorders, often resulting in severe pain or disability and the need for joint replacements. There have been few longitudinal studies of progression to inform individual prognoses in primary care.
To describe the degree of progression and investigate predictors of change in hip or knee pain and disability.
Design of study
Prospective community-based cohort.
An age–sex stratified survey of 27 000 people registered with 40 general practices in Avon and Somerset yielded 2437 reporting hip and/or knee symptoms at baseline (1992–1994). A 25% random sample of 587 individuals was followed up between 1998 and 1999.
Pain or disability was measured at baseline and follow-up using the New Zealand score. For the worst joint according to the New Zealand score at baseline, hip and knee problems were analysed separately. Regression models ascertained characteristics of non-responders and factors associated with change in scores. Seven sociodemographic, seven comorbidity, and two healthcare utilisation variables were considered.
Generally pain and disability worsened over the 7 years, but 35% and 29% of those initially reporting hip and knee pain respectively had improved. Reporting ‘other health problems’ was associated with greater deterioration for both hip and knee disease, as was cardiovascular morbidity for hip disease and lower social class, being retired, hypertension, and higher body mass index for knee disease. Deteriorations in scores were strongly associated with individuals consulting their GP about joint problems.
Osteoarthritis does not invariably deteriorate, but when it does social as well as biological factors appear to be important. These findings may aid outcome prediction. Future research on osteoarthritis should be conducted within a biopsychosocial rather than a purely biological paradigm.
PMCID: PMC1463091  PMID: 15808036
disability evaluation; disease progression; New Zealand score; osteoarthritis; pain; projections and predictions
9.  Within-person variability in calculated risk factors: Comparing the aetiological association of adiposity ratios with risk of coronary heart disease 
Background Within-person variability in measured values of a risk factor can bias its association with disease. We investigated the extent of regression dilution bias in calculated variables and its implications for comparing the aetiological associations of risk factors.
Methods Using a numerical illustration and repeats from 42 300 individuals (12 cohorts), we estimated regression dilution ratios (RDRs) in calculated risk factors [body-mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)] and in their components (height, weight, waist circumference, and hip circumference), assuming the long-term average exposure to be of interest. Error-corrected hazard ratios (HRs) for risk of coronary heart disease (CHD) were compared across adiposity measures per standard-deviation (SD) change in: (i) baseline and (ii) error-corrected levels.
Results RDRs in calculated risk factors depend strongly on the RDRs, correlation, and comparative distributions of the components of these risk factors. For measures of adiposity, the RDR was lower for WHR [RDR: 0.72 (95% confidence interval 0.65–0.80)] than for either of its components [waist circumference: 0.87 (0.85–0.90); hip circumference: 0.90 (0.86–0.93) or for BMI: 0.96 (0.93–0.98) and WHtR: 0.87 (0.85–0.90)], predominantly because of the stronger correlation and more similar distributions observed between waist circumference and hip circumference than between height and weight or between waist circumference and height. Error-corrected HRs for BMI, waist circumference, WHR, and WHtR, were respectively 1.24, 1.30, 1.44, and 1.32 per SD change in baseline levels of these variables, and 1.24, 1.27, 1.35, and 1.30 per SD change in error-corrected levels.
Conclusions The extent of within-person variability relative to between-person variability in calculated risk factors can be considerably larger (or smaller) than in its components. Aetiological associations of risk factors should be compared through the use of error-corrected HRs per SD change in error-corrected levels of these risk factors.
PMCID: PMC3733701  PMID: 23918853
Regression dilution bias; measurement error; within-person variation; adiposity measures
10.  Body Fat Distribution and Risk of Premenopausal Breast Cancer in the Nurses’ Health Study II 
Body mass index is inversely associated with risk of premenopausal breast cancer, but the underlying mechanisms for this association are poorly understood. Abdominal adiposity is associated with metabolic and hormonal changes, many of which have been associated with the risk of premenopausal breast cancer. We investigated the association between body fat distribution, assessed in 1993 by self-reported waist circumference, hip circumference, and waist to hip ratio, and the incidence of premenopausal breast cancer in the Nurses’ Health Study II. Cox proportional hazards regression models were used to calculate hazard ratios and 95% confidence intervals (CIs). Statistical tests were two-sided. During 426 164 person-years of follow-up from 1993 to 2005, 620 cases of breast cancer were diagnosed among 45 799 women. Hormone receptor status information was available for 84% of the breast cancers. The age-standardized incidence rates of breast cancer were 131 per 100 000 person-years among those in the lowest quintile of waist circumference and 136 per 100 000 person-years among those in the highest quintile. No statistically significant associations were found between waist circumference, hip circumference, or the waist to hip ratio and risk of breast cancer. However, each of the three body fat distribution measures was statistically significantly associated with greater incidence of estrogen receptor (ER)–negative breast cancer. The multivariable-adjusted hazard ratios of ER-negative breast cancer for the highest vs the lowest quintile of each body fat distribution measure were 2.75 (95% CI = 1.15 to 6.54; Ptrend = .05) for waist circumference, 2.40 (95% CI = 0.95 to 6.08; Ptrend = .26) for hip circumference, and 1.95 (95% CI = 1.10 to 3.46; Ptrend = .01) for waist to hip ratio. Our findings suggest that body fat distribution does not play an important role in the overall incidence of premenopausal breast cancer but is associated with an increased risk for ER-negative breast cancer.
PMCID: PMC3107569  PMID: 21163903
11.  Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci 
Liu, Ching-Ti | Monda, Keri L. | Taylor, Kira C. | Lange, Leslie | Demerath, Ellen W. | Palmas, Walter | Wojczynski, Mary K. | Ellis, Jaclyn C. | Vitolins, Mara Z. | Liu, Simin | Papanicolaou, George J. | Irvin, Marguerite R. | Xue, Luting | Griffin, Paula J. | Nalls, Michael A. | Adeyemo, Adebowale | Liu, Jiankang | Li, Guo | Ruiz-Narvaez, Edward A. | Chen, Wei-Min | Chen, Fang | Henderson, Brian E. | Millikan, Robert C. | Ambrosone, Christine B. | Strom, Sara S. | Guo, Xiuqing | Andrews, Jeanette S. | Sun, Yan V. | Mosley, Thomas H. | Yanek, Lisa R. | Shriner, Daniel | Haritunians, Talin | Rotter, Jerome I. | Speliotes, Elizabeth K. | Smith, Megan | Rosenberg, Lynn | Mychaleckyj, Josyf | Nayak, Uma | Spruill, Ida | Garvey, W. Timothy | Pettaway, Curtis | Nyante, Sarah | Bandera, Elisa V. | Britton, Angela F. | Zonderman, Alan B. | Rasmussen-Torvik, Laura J. | Chen, Yii-Der Ida | Ding, Jingzhong | Lohman, Kurt | Kritchevsky, Stephen B. | Zhao, Wei | Peyser, Patricia A. | Kardia, Sharon L. R. | Kabagambe, Edmond | Broeckel, Ulrich | Chen, Guanjie | Zhou, Jie | Wassertheil-Smoller, Sylvia | Neuhouser, Marian L. | Rampersaud, Evadnie | Psaty, Bruce | Kooperberg, Charles | Manson, JoAnn E. | Kuller, Lewis H. | Ochs-Balcom, Heather M. | Johnson, Karen C. | Sucheston, Lara | Ordovas, Jose M. | Palmer, Julie R. | Haiman, Christopher A. | McKnight, Barbara | Howard, Barbara V. | Becker, Diane M. | Bielak, Lawrence F. | Liu, Yongmei | Allison, Matthew A. | Grant, Struan F. A. | Burke, Gregory L. | Patel, Sanjay R. | Schreiner, Pamela J. | Borecki, Ingrid B. | Evans, Michele K. | Taylor, Herman | Sale, Michele M. | Howard, Virginia | Carlson, Christopher S. | Rotimi, Charles N. | Cushman, Mary | Harris, Tamara B. | Reiner, Alexander P. | Cupples, L. Adrienne | North, Kari E. | Fox, Caroline S.
PLoS Genetics  2013;9(8):e1003681.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Author Summary
Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.
PMCID: PMC3744443  PMID: 23966867
12.  Effect of leisure time physical activity on severe knee or hip osteoarthritis leading to total joint replacement: a population-based prospective cohort study 
Studies on leisure time physical activity as risk factor or protective factor for knee or hip osteoarthritis (OA) show divergent results. Longitudinal prospective studies are needed to clarify the association of physical activity with future OA. The aim was to explore in a prospective population-based cohort study the influence of leisure time physical activity on severe knee or hip OA, defined as knee or hip replacement due to OA.
Leisure time physical activity was reported by 28320 participants (mean age 58 years (SD 7.6), 60% women) at baseline. An overall leisure time physical activity score, taking both duration and intensity of physical activities into account, was created. The most commonly reported activities were also used for analysis. The incidence of knee or hip replacement due to OA over 11 years was monitored by linkage with the Swedish hospital discharge register. Cox’s proportional hazards model (crude and adjusted for potential confounding factors) was used to assess the incidence of total joint replacement, or osteotomy (knee), in separate analyses of leisure time physical activity.
There was no significant overall association between leisure time physical activity and risk for knee or hip replacement due to OA over the 11-year observation time. For women only, the adjusted RR (95% CI) for hip replacement was 0.66 (0.48, 0.89) (fourth vs. first quartile), indicating a lower risk of hip replacement in those with the highest compared with the lowest physical activity. The most commonly reported activities were walking, bicycling, using stairs, and gardening. Walking was associated with a lower risk of hip replacement (adjusted RR 0.76 (95% CI 0.61, 0.94), specifically for women (adjusted RR 0.75 (95% CI 0.57, 0.98)).
In this population-based study of middle-aged men and women, leisure time physical activity showed no consistent overall relationship with incidence of severe knee or hip OA, defined as joint replacement due to OA, over 11 years. For women, higher leisure time physical activity may have a protective role for the incidence of hip replacement. Walking may have a protective role for hip replacement, specifically for women.
PMCID: PMC3462680  PMID: 22595023
Osteoarthritis; Arthroplasty; Exercise; Workload; Risk factors
13.  Anthropometric Correlates of Total Body Fat, Abdominal Adiposity, and Cardiovascular Disease Risk Factors in a Biracial Sample of Men and Women 
Mayo Clinic Proceedings  2012;87(5):452-460.
To investigate associations between anthropometric measurements and total body fat, abdominal adipose tissue, and cardiovascular disease risk factors in a large biracial sample.
Patients and Methods
This study is limited to cross-sectional analyses of data from participants attending a baseline visit between January 26, 1996, and February 1, 2011. The sample included 2037 individuals aged 18 to 69 years: 488 African American women (24%), 686 white women (34%), 196 African American men (9%), and 667 white men (33%). Anthropometry included weight; hip circumference; waist circumference; waist-hip, waist-height, and weight-height ratios; body adiposity index; and body mass index. Body fat and percentage of fat were measured by dual-energy x-ray absorptiometry, and abdominal visceral and subcutaneous adipose tissue were measured by computed tomography. Bivariate correlations, logistic regression models, and receiver operator characteristic curves were used, and analyses were stratified by sex and race.
In each sex-by-race group, all anthropometric measures were highly correlated with percentage of fat, fat mass, and subcutaneous adipose tissue and moderately correlated with visceral adipose tissue, with the exception of the waist-hip ratio. The odds of having an elevated cardiometabolic risk were increased more than 2-fold per SD increase for most anthropometric variables, and the areas under the curve for each anthropometric measure were significantly greater than 0.5.
Several common anthropometric measures were moderately to highly correlated with total body fat, abdominal fat, and cardiovascular disease risk factors in a biracial sample of women and men. This comprehensive analysis provides evidence of the linkage between simple anthropometric measurements and the purported pathways between adiposity and health.
PMCID: PMC3498102  PMID: 22560524
AUC, area under the curve; BAI, body adiposity index; BMI, body mass index; CT, computed tomography; CVD, cardiovascular disease; DXA, dual-energy x-ray absorptiometry; HC, hip circumference; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCLS, Pennington Center Longitudinal Study; ROC, receiver operating characteristic; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; WC, waist circumference
14.  Long-Term Risk of Incident Type 2 Diabetes and Measures of Overall and Regional Obesity: The EPIC-InterAct Case-Cohort Study 
PLoS Medicine  2012;9(6):e1001230.
A collaborative re-analysis of data from the InterAct case-control study conducted by Claudia Langenberg and colleagues has established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index.
Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).
Methods and Findings
The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5–22.4 kg/m2) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m2) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50–103 per 1,000 person-years in men and 28–74 per 1,000 person-years in women).
WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, more than 350 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
A high body mass index (BMI, a measure of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is a strong predictor of type 2 diabetes. Although the risk of diabetes is greatest in obese people (who have a BMI of greater than 30 kg/m2), many of the people who develop diabetes are overweight—they have a BMI of 25–30 kg/m2. Healthy eating and exercise reduce the incidence of diabetes in high-risk individuals, but it is difficult and expensive to provide all overweight and obese people with individual lifestyle advice. Ideally, a way is needed to distinguish between people with high and low risk of developing diabetes at different levels of BMI. Waist circumference is a measure of fat distribution that has the potential to quantify diabetes risk among people with different BMIs because it estimates the amount of fat around the abdominal organs, which also predicts diabetes development. In this case-cohort study, the researchers use data from the InterAct study (which is investigating how genetics and lifestyle interact to affect diabetes risk) to estimate the long-term risk of type 2 diabetes associated with BMI and waist circumference. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease and in a randomly chosen subcohort.
What Did the Researchers Do and Find?
The researchers estimated the association of BMI and waist circumference with type 2 diabetes from baseline measurements of the weight, height, and waist circumference of 12,403 people who subsequently developed type 2 diabetes and a subcohort of 16,154 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC). Both risk factors were independently associated with type 2 diabetes risk, but waist circumference was a stronger risk factor in women than in men. Obese men (BMI greater than 35 kg/m2) with a high waist circumference (greater than 102 cm) were 22 times more likely to develop diabetes than men with a low normal weight (BMI 18.5–22.4 kg/m2) and a low waist circumference (less than 94 cm); obese women with a waist circumference of more than 88 cm were 31.8 times more likely to develop type 2 diabetes than women with a low normal weight and waist circumference (less than 80 cm). Importantly, among overweight people, waist circumference measurements identified a subgroup of overweight people (those with a high waist circumference) whose 10-year cumulative incidence of type 2 diabetes was similar to that of obese people.
What Do These Findings Mean?
These findings indicate that, among people of European descent, waist circumference is independently and strongly associated with type 2 diabetes, particularly among women. Additional studies are needed to confirm this association in other ethnic groups. Targeted measurement of waist circumference in overweight individuals (who now account for a third of the US and UK adult population) could be an effective strategy for the prevention of diabetes because it would allow the identification of a high-risk subgroup of people who might benefit from individualized lifestyle advice.
Additional Information
Please access these web sites via the online version of this summary at
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public, including detailed information on diabetes prevention (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (including some information in Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes, about the prevention of type 2 diabetes, and about obesity; it also includes peoples stories about diabetes and about obesity
The charity Diabetes UK also provides detailed information for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes
More information on the InterAct study is available
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention and about obesity (in English and Spanish)
PMCID: PMC3367997  PMID: 22679397
15.  Association of Hip Circumference With Incident Diabetes and Coronary Heart Disease 
American Journal of Epidemiology  2009;169(7):837-847.
When waist circumference is taken into account, larger hip circumference is associated with reduced risk factors for diabetes and cardiovascular disease. The authors investigated the prospective association of hip circumference with type 2 diabetes and coronary heart disease (CHD) incidence in a biracial cohort of men and women in 4 US communities. A total of 10,767 participants from the Atherosclerosis Risk in Communities (ARIC) study were followed from 1987 to 1998. Hip and waist circumferences and body mass index (BMI) were modeled separately and mutually in association with incident diabetes and CHD by using proportional hazards regression. After adjustment for age, race, sex, and clinical center, hip circumference was positively associated with incident diabetes. However, after further controlling for waist circumference, BMI, and confounding variables, successive quintiles of hip circumference were associated with a statistically significant reduced hazard of incident diabetes (hazard ratios = 1.00, 0.79, 0.60, 0.44, 0.41). Similarly, successive quintiles of hip circumference were associated with a statistically significant reduced hazard of CHD after controlling for waist circumference, BMI, and confounding variables (hazard ratios = 1.00, 0.92, 0.75, 0.63, 0.50). Although excess adiposity is a general risk factor for diabetes and CHD, for a given BMI and waist circumference, greater hip circumference appears to lessen the risk of diabetes and CHD.
PMCID: PMC2727216  PMID: 19224980
adiposity; anthropometry; coronary disease; diabetes mellitus
16.  Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women 
PLoS Genetics  2012;8(5):e1002695.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Author Summary
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
PMCID: PMC3349734  PMID: 22589738
17.  Application of alternative anthropometric measurements to predict metabolic syndrome 
Clinics  2014;69(5):347-353.
The association between rarely used anthropometric measurements (e.g., mid-upper arm, forearm, and calf circumference) and metabolic syndrome has not been proven. The aim of this study was to assess whether mid-upper arm, forearm, calf, and waist circumferences, as well as waist/height ratio and waist-to-hip ratio, were associated with metabolic syndrome.
We enrolled 387 subjects (340 women, 47 men) who were admitted to the obesity outpatient department of Istanbul Medeniyet University Goztepe Training and Research Hospital between September 2010 and December 2010. The following measurements were recorded: waist circumference, hip circumference, waist/height ratio, waist-to-hip ratio, mid-upper arm circumference, forearm circumference, calf circumference, and body composition. Fasting blood samples were collected to measure plasma glucose, lipids, uric acid, insulin, and HbA1c.
The odds ratios for visceral fat (measured via bioelectric impedance), hip circumference, forearm circumference, and waist circumference/hip circumference were 2.19 (95% CI, 1.30-3.71), 1.89 (95% CI, 1.07-3.35), 2.47 (95% CI, 1.24-4.95), and 2.11(95% CI, 1.26-3.53), respectively. The bioelectric impedance-measured body fat percentage correlated with waist circumference only in subjects without metabolic syndrome; the body fat percentage was negatively correlated with waist circumference/hip circumference in the metabolic syndrome group. All measurements except for forearm circumference were equally well correlated with the bioelectric impedance-measured body fat percentages in both groups. Hip circumference was moderately correlated with bioelectric impedance-measured visceral fat in subjects without metabolic syndrome. Muscle mass (measured via bioelectric impedance) was weakly correlated with waist and forearm circumference in subjects with metabolic syndrome and with calf circumference in subjects without metabolic syndrome.
Waist circumference was not linked to metabolic syndrome in obese and overweight subjects; however, forearm circumference, an unconventional but simple and appropriate anthropometric index, was associated with metabolic syndrome and bioelectric impedance-measured visceral fat, hip circumference, and waist-to-hip ratio.
PMCID: PMC4012236  PMID: 24838901
Metabolic Syndrome; Anthropometric Measurements; Body Composition
18.  Association Between Adiposity in Midlife and Older Age and Risk of Diabetes in Older Adults 
Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.
To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.
Design, Setting, and Participants
Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.
Main Outcome Measure
Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.
Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (±2 kg), those who gained the most weight from 50 years of age to baseline (≥9 kg), and from baseline to the third follow-up visit (≥6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.
Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
PMCID: PMC3047456  PMID: 20571017
19.  Waist-to-Height Ratio as a Predictor of Coronary Heart Disease among Women 
Epidemiology (Cambridge, Mass.)  2009;20(3):361-366.
The aim of our study is to prospectively evaluate and compare the waist circumference-to-height ratio (WHtR) to waist-hip ratio, waist circumference, and body mass index as predictors of subsequent coronary heart disease (CHD) in a group of predominantly post-menopausal women.
The data comes from a prospective cohort study. The included subjects were 45563 women from the Nurses' Health Study cohort, aged 40-65 years in 1986, who were free of heart disease, stroke and cancer. Waist circumference, hip circumference, height, weight, age, and other covariates were collected by questionnaire. The primary endpoint was incident coronary heart disease that was reported by June 2002. Areas under the receiver operating characteristic curves (AUC) were estimated non-parametrically for each of anthropometric measures, and differences between that for WHtR and the other measures, and corresponding 95% confidence intervals were estimated. Cox proportional hazard models were used to estimate the relationships with risk of CHD.
Waist-height ratio, waist-hip ratio and waist circumference were similar in predicting subsequent risk of CHD. All three waist derived measures were superior to BMI in predicting CHD. The unadjusted AUC (95% Confidence Interval) were 0.62 (0.60,0.64) for WHtR, 0.63 (0.61,0.65) for waist-hip ratio, 0.62 (0.60,0.64) for waist-circumference, and 0.57 (0.55,0.59) for body mass index.
Waist-height ratio is comparable to waist circumference and waist-hip ratio for prediction of coronary heart disease incidence among middle-aged and older women, but superior to BMI. Future studies are warranted to corroborate these results in other populations.
PMCID: PMC4012298  PMID: 19289960
20.  Different anthropometric adiposity measures and their association with cardiovascular disease risk factors: a meta-analysis 
Netherlands Heart Journal  2012;20(5):208-218.
To investigate which anthropometric adiposity measure has the strongest association with cardiovascular disease (CVD) risk factors in Caucasian men and women without a history of CVD.
Systematic review and meta-analysis.
We searched databases for studies reporting correlations between anthropometric adiposity measures and CVD risk factors in Caucasian subjects without a history of CVD. Body mass index (BMI), waist circumference, waist-to-hip ratio, waist-to-height ratio and body fat percentage were considered the anthropometric adiposity measures. Primary CVD risk factors were: systolic blood pressure, diastolic blood pressure, high density lipoprotein (HDL) cholesterol, triglycerides and fasting glucose. Two independent reviewers performed abstract, full text and data selection.
Twenty articles were included describing 21,618 males and 24,139 females. Waist circumference had the strongest correlation with all CVD risk factors for both men and women, except for HDL and LDL in men. When comparing BMI with waist circumference, the latter showed significantly better correlations to CVD risk factors, except for diastolic blood pressure in women and HDL and total cholesterol in men.
We recommend the use of waist circumference in clinical and research studies above other anthropometric adiposity measures, especially compared with BMI, when evaluating CVD risk factors.
PMCID: PMC3346869  PMID: 22231153
Meta-analysis; Cardiovascular disease risk factors; Anthropometric; Adiposity; Waist circumference; Medicine & Public Health; Medicine/Public Health, general
21.  Incidence and Risk Factors of Prosthetic Joint Infection After Total Hip or Knee Replacement in Patients With Rheumatoid Arthritis 
Arthritis and rheumatism  2008;59(12):1713-1720.
Prosthetic joint infection is one of the most dreaded complications after total joint arthroplasty, a common procedure in patients with rheumatoid arthritis (RA). We conducted a study to evaluate potential risk factors of prosthetic joint infection and to clarify if RA is an independent predictor of this complication.
This study included all patients with RA who underwent total hip or knee replacement at the Mayo Clinic Rochester between January 1996 and June 2004. The association of potential risk factors with prosthetic joint infection was examined using Cox models. A matched cohort of patients with osteoarthritis (OA) was assembled to determine whether RA is an independent risk factor for prosthetic joint infection.
We identified 462 patients with RA who underwent a total of 657 hip or knee replacements. Overall, 23 (3.7%) joint arthroplasties were complicated by an infection during a mean ± SD followup of 4.3 ± 2.4 years. Revision arthroplasty (hazard ratio [HR] 2.99, 95% confidence interval [95% CI] 1.02–8.75) and a previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87–16.14) were significant predictors of postoperative prosthetic joint infection. Comparison of RA patients with a matched cohort of OA patients identified an increased risk of prosthetic joint infections (HR 4.08, 95% CI 1.35–12.33) in patients with RA.
Patients with RA who undergo total hip or knee replacement are at increased risk of prosthetic joint infection, which is further increased in the setting of revision arthroplasty and a previous prosthetic joint infection. These findings highlight the importance of perioperative prophylactic measures and vigilance during the postoperative period.
PMCID: PMC3923416  PMID: 19035425
22.  Body mass index and risk of perioperative cardiovascular adverse events and mortality in 34,744 Danish patients undergoing hip or knee replacement 
Acta Orthopaedica  2014;85(5):456-462.
Background and purpose
Obesity is a risk factor for osteoarthritis in the lower limb, yet the cardiovascular risks associated with obesity in hip or knee replacement surgery are unknown. We examined associations between body mass index (BMI) and the risk of a major adverse cardiovascular event (MACE: ischemic stroke, acute myocardial infarction, or cardiovascular death) or the risk of all-cause mortality in a nationwide Danish cohort of patients who underwent primary hip or knee replacement surgery.
Using Danish nationwide registries, we identified 34,744 patients aged ≥ 20 years who underwent elective primary hip or knee replacement surgery between 2005 and 2011. We used multivariable Cox regression models to calculate the 30-day risks of MACE and mortality associated with 5 BMI groups (underweight (BMI < 18.5 kg/m2), normal weight (18.5–24 kg/m2), overweight (25–29 kg/m2), obese 1 (30–34 kg/m2), and obese 2 (≥ 35 kg/m2)).
In total, 232 patients (0.7%) had a MACE and 111 (0.3%) died. Compared with overweight, adjusted hazard ratios (HRs) were 1.2 (95% CI: 0.4–3.3), 1.3 (0.95–1.8), 1.6 (1.1–2.2), and 1.0 (0.6–1.9) for underweight, normal weight, obese 1, and obese 2 regarding MACE. Regarding mortality, the corresponding HRs were 7.0 (2.8–15), 2.0 (1.2–3.2), 1.5 (0.9–2.7), and 1.9 (0.9–4.2). Cubic splines suggested a significant U-shaped relationship between BMI and risks with nadir around 27–28.
In an unselected cohort of patients undergoing elective primary hip or knee replacement surgery, U-shaped risks of perioperative MACE and mortality were found in relation to BMI. Patients within the extreme ranges of BMI may warrant further attention.
PMCID: PMC4164861  PMID: 24954493
23.  Predictors of mortality following primary hip and knee replacement in the aged 
Acta Orthopaedica  2013;84(1):44-53.
Background and purpose
High age is associated with increased postoperative mortality, but the factors that predict mortality in older hip and knee replacement recipients are not known.
Preoperative clinical and operative data on 1,998 primary total hip and knee replacements performed for osteoarthritis in patients aged ≥ 75 years in a single institution were collected from a joint replacement database and compoared with mortality data. Average follow-up was 4.2 (2.2–7.6) years for the patients who survived. Factors associated with mortality were analyzed using Cox regression analysis, with adjustment for age, sex, operated joint, laterality, and anesthesiological risk score.
Mortality was 0.15% at 30 days, 0.35% at 90 days, 1.60% at 1 year, 7.6% at 3 years, and 16% at 5 years, and was similar following hip and knee replacement. Higher age, male sex, American Society of Anesthesiologists risk score of > 2, use of walking aids, preoperative walking restriction (inability to walk or ability to walk indoors only, compared to ability to walk > 1 km), poor clinical condition preoperatively (based on clinical hip and knee scores or clinical severity of osteoarthritis), preoperative anemia, severe renal insufficiency, and use of blood transfusions were associated with higher mortality. High body mass index had a protective effect in patients after hip replacement.
Postoperative mortality is low in healthy old joint replacement recipients. Comorbidities and functional limitations preoperatively are associated with higher mortality and warrant careful consideration before proceeding with joint replacement surgery.
PMCID: PMC3584602  PMID: 23244785
24.  Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study 
Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use.
Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed.
For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime.
An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.
PMCID: PMC3446339  PMID: 22583394
25.  Change in Body Size and Mortality: Results from the Melbourne Collaborative Cohort Study 
PLoS ONE  2014;9(7):e99672.
The association between change in weight or body mass index, and mortality is widely reported, however, both measures fail to account for fat distribution. Change in waist circumference, a measure of central adiposity, in relation to mortality has not been studied extensively.
We investigated the association between mortality and changes in directly measured waist circumference, hips circumference and weight from baseline (1990–1994) to wave 2 (2003–2007) in a prospective cohort study of people aged 40–69 years at baseline. Cox regression, with age as the time metric and follow-up starting at wave 2, adjusted for confounding variables, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for change in body size in relation to mortality from all causes, cardiovascular disease and cancer.
There were 1465 deaths (109 cancer, 242 cardiovascular disease) identified during an average 7.7 years of follow-up from 21 298 participants. Compared to minimal increase in body size, loss of waist circumference (HR: 1.26; 95% CI: 1.09–1.47), weight (1.80; 1.54–2.11), or hips circumference (1.35; 1.15–1.57) were associated with an increased risk of all-cause mortality, particularly for older adults. Weight loss was associated with cardiovascular disease mortality (2.40; 1.57–3.65) but change in body size was not associated with obesity-related cancer mortality.
This study confirms the association between weight loss and increased mortality from all-causes for older adults. Based on evidence from observational cohort studies, weight stability may be the recommended option for most adults, especially older adults.
PMCID: PMC4079561  PMID: 24988430

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