Proteomic associations with forced expiratory volume - a Mendelian randomisation study.

A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.

Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study.

Objective: To describe the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in a large population-based study of elderly Icelanders, with particular reference to weight-related factors and the metabolic syndrome.Method: The study population comprised 5321 participants aged 68-96 years (2276 males, mean ± sd age 76 ± 5 , and 3045 females, age 77 ± 6) from the AGES-Reykjavik Study. DISH diagnosis was based on computed tomography (CT) scans, and interpreted strictly by the Resnick criteria and additional suggestions for CT interpretation by Oudkerk et al. Radiology readings were taken by a radiology resident and sample readings by two experienced radiologists.Results: A diagnosis of DISH was made in 13.7% of males and 2.8% of females. There was no association with age, but a strong association was seen with the metabolic syndrome [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.69-2.64, p = 3.9 × 10-11]. Among the components of the metabolic syndrome, the association with DISH was significant for the insulin resistance criterion (OR 1.66, 95% CI 1.32-2.01, p < 0.001) and the body mass index (BMI) criterion (OR 2.16, 95% CI 1.70-2.74, p < 0.001). Other weight-related variables (midlife BMI, weight, and abdominal circumference) showed similar associations.Conclusions: This study, which to our knowledge is the largest published study on the prevalence of DISH, shows an association with the metabolic syndrome, particularly with the insulin resistance and BMI criteria. This is analogous with previous reports linking DISH with metabolic causes. In this age category, we did not observe any increase in prevalence with age.

Quantitative 3D imaging parameters improve prediction of hip osteoarthritis outcome.

Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography-a fast, readily available clinical technique-that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies.

Biofidelic finite element models for accurately classifying hip fracture in a retrospective clinical study of elderly women from the AGES Reykjavik cohort.

Clinical retrospective studies have only reported limited improvements in hip fracture classification accuracy using finite element (FE) models compared to conventional areal bone mineral density (aBMD) measurements. A possible explanation is that state-of-the-art quasi-static models do not estimate patient-specific loads. A novel FE modeling technique was developed to improve the biofidelity of simulated impact loading from sideways falling. This included surrogate models of the pelvis, lower extremities, and soft tissue that were morphed based on subject anthropometrics. Hip fracture prediction models based on aBMD and FE measurements were compared in a retrospective study of 254 elderly female subjects from the AGES-Reykjavik study. Subject fragility ratio (FR) was defined as the ratio between the ultimate forces of paired biofidelic models, one with linear elastic and the other with non-linear stress-strain relationships in the proximal femur. The expected end-point value (EEV) was defined as the FR weighted by the probability of one sideways fall over five years, based on self-reported fall frequency at baseline. The change in maximum volumetric strain (ΔMVS) on the surface of the femoral neck was calculated between time of ultimate femur force and 90% post-ultimate force in order to assess the extent of tensile tissue damage present in non-linear models. After age-adjusted logistic regression, the area under the receiver-operator curve (AUC) was highest for ΔMVS (0.72), followed by FR (0.71), aBMD (0.70), and EEV (0.67), however the differences between FEA and aBMD based prediction models were not deemed statistically significant. When subjects with no history of falling were excluded from the analysis, thus artificially assuming that falls were known a priori with no uncertainty, a statistically significant difference in AUC was detected between ΔMVS (0.85), and aBMD (0.74). Multivariable linear regression suggested that the variance in maximum elastic femur force was best explained by femoral head radius, pelvis width, and soft tissue thickness (R2 = 0.79; RMSE = 0.46 kN; p < 0.005). Weighting the hip fracture prediction models based on self-reported fall frequency did not improve the models' sensitivity, however excluding non-fallers lead to significant differences between aBMD and FE based models. These findings suggest that an accurate assessment of fall probability is necessary for accurately identifying individuals predisposed to hip fracture.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Exploring potential mortality reductions in 9 European countries by improving diet and lifestyle: A modelling approach.

BACKGROUND: Coronary heart disease (CHD) death rates have fallen across most of Europe in recent decades. However, substantial risk factor reductions have not been achieved across all Europe. Our aim was to quantify the potential impact of future policy scenarios on diet and lifestyle on CHD mortality in 9 European countries. METHODS: We updated the previously validated IMPACT CHD models in 9 European countries and extended them to 2010-11 (the baseline year) to predict reductions in CHD mortality to 2020(ages 25-74years). We compared three scenarios: conservative, intermediate and optimistic on smoking prevalence (absolute decreases of 5%, 10% and 15%); saturated fat intake (1%, 2% and 3% absolute decreases in % energy intake, replaced by unsaturated fats); salt (relative decreases of 10%, 20% and 30%), and physical inactivity (absolute decreases of 5%, 10% and 15%). Probabilistic sensitivity analyses were conducted. RESULTS: Under the conservative, intermediate and optimistic scenarios, we estimated 10.8% (95% CI: 7.3-14.0), 20.7% (95% CI: 15.6-25.2) and 29.1% (95% CI: 22.6-35.0) fewer CHD deaths in 2020. For the optimistic scenario, 15% absolute reductions in smoking could decrease CHD deaths by 8.9%-11.6%, Salt intake relative reductions of 30% by approximately 5.9-8.9%; 3% reductions in saturated fat intake by 6.3-7.5%, and 15% absolute increases in physical activity by 3.7-5.3%. CONCLUSIONS: Modest and feasible policy-based reductions in cardiovascular risk factors (already been achieved in some other countries) could translate into substantial reductions in future CHD deaths across Europe. However, this would require the European Union to more effectively implement powerful evidence-based prevention policies.

Individualised risk assessment for diabetic retinopathy and optimisation of screening intervals: a scientific approach to reducing healthcare costs.

OBJECTIVE: To validate a mathematical algorithm that calculates risk of diabetic retinopathy progression in a diabetic population with UK staging (R0-3; M1) of diabetic retinopathy. To establish the utility of the algorithm to reduce screening frequency in this cohort, while maintaining safety standards. RESEARCH DESIGN AND METHODS: The cohort of 9690 diabetic individuals in England, followed for 2 years. The algorithms calculated individual risk for development of preproliferative retinopathy (R2), active proliferative retinopathy (R3A) and diabetic maculopathy (M1) based on clinical data. Screening intervals were determined such that the increase in risk of developing certain stages of retinopathy between screenings was the same for all patients and identical to mean risk in fixed annual screening. Receiver operating characteristic curves were drawn and area under the curve calculated to estimate the prediction capability. RESULTS: The algorithm predicts the occurrence of the given diabetic retinopathy stages with area under the curve =80% for patients with type II diabetes (CI 0.78 to 0.81). Of the cohort 64% is at less than 5% risk of progression to R2, R3A or M1 within 2 years. By applying a 2 year ceiling to the screening interval, patients with type II diabetes are screened on average every 20 months, which is a 40% reduction in frequency compared with annual screening. CONCLUSIONS: The algorithm reliably identifies patients at high risk of developing advanced stages of diabetic retinopathy, including preproliferative R2, active proliferative R3A and maculopathy M1. Majority of patients have less than 5% risk of progression between stages within a year and a small high-risk group is identified. Screening visit frequency and presumably costs in a diabetic retinopathy screening system can be reduced by 40% by using a 2 year ceiling. Individualised risk assessment with 2 year ceiling on screening intervals may be a pragmatic next step in diabetic retinopathy screening in UK, in that safety is maximised and cost reduced by about 40%.

The incidence of a first major osteoporotic fracture in Iceland and implications for FRAX.

SUMMARY: Based on an extensive cohort study over 25 years, the present study supports the assumption that major osteoporotic fractures can be reasonably predicted from hip fracture rates. INTRODUCTION: The construct for FRAX models depends on algorithms to adjust for double counting of fracture outcomes in some models and in others, to estimate the incidence of a major fracture from hip fracture rates. The aim of the present study was to test the validity of these algorithms in a large prospective cohort. METHODS: The incidence of hip, clinical spine, distal forearm, and humerus fracture was determined in the prospective and ongoing population-based Reykjavik Study with follow up of 257,001 person-years. The incidence of a first major fracture was compared with the correction factors used in FRAX to adjust the incidence of several fracture outcomes for double counting. In addition, the incidence of a major osteoporotic fracture estimated from the Icelandic hip fracture rates was compared with the Malmo ratios used in FRAX. RESULTS: The adjustments necessary to account for multiple fracture outcomes were similar to those previously derived from Sweden. Additionally, incidence of a first major osteoporotic fracture was similar to that derived for FRAX models. CONCLUSION: The findings of the present study support the algorithms used in FRAX to estimate the incidence of a first major fracture and the predictive value of hip fracture for other major fractures.