Publications by authors named "Liubov Arbeeva"

46 Publications

The Prevalence of Knee Symptoms, Radiographic, and Symptomatic Osteoarthritis at Four Time Points: The Johnston County Osteoarthritis Project, 1999-2018.

ACR Open Rheumatol 2021 Jul 10. Epub 2021 Jul 10.

University of North Carolina at Chapel Hill.

Objective: To describe point prevalence of knee symptoms, radiographic knee osteoarthritis (rKOA), severe rKOA, and symptomatic rKOA at four time points in the longitudinal, population-based Johnston County Osteoarthritis Project (JoCo OA).

Methods: Data were from 2573 JoCo OA participants with up to 18 years of follow-up (1999-2018) and standardized fixed-flexion knee radiographs read by a single, reliable expert musculoskeletal radiologist. The four outcomes were 1) self-reported knee symptoms, defined by "On most days, do you have pain, aching, or stiffness in your right/left knee?"; 2) rKOA, defined as a Kellgren-Lawrence grade (KLG) of 2 to 4); 3) severe rKOA, defined as a KLG of 3 or 4; and 4) symptomatic rKOA, defined as both symptoms and rKOA in the same joint. Weighted prevalence estimates and 95% confidence intervals (CIs) were generated overall and by age group, sex, race, and body mass index (BMI).

Results: Most recently (2017-2018, T4), the overall prevalence (percentage) of knee symptoms, rKOA, severe rKOA, and symptomatic rKOA was 41% (95% CI: 35-47%), 61% (95% CI: 56-67%), 35% (95% CI: 30-40%), and 30% (95% CI: 24-35%), respectively. From time point T1 to T4, prevalence increased for rKOA, severe rKOA, and symptomatic rKOA but not for knee symptoms. The prevalence of both severe rKOA (17-39%) and symptomatic rKOA (23-30%) was consistently higher among women. The prevalence of all outcomes was higher among those with higher BMI and among Black participants at all time points, particularly rKOA (35-69%) and severe rKOA (22-46%).

Conclusion: These updated estimates demonstrate a large and increasing burden of knee OA, particularly among women and Black individuals.
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http://dx.doi.org/10.1002/acr2.11295DOI Listing
July 2021

Associations between baseline and longitudinal semi-automated quantitative joint space width at the hip and incident hip osteoarthritis: Data from a community-based cohort.

Arthritis Care Res (Hoboken) 2021 Jul 5. Epub 2021 Jul 5.

Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.

Objective: To evaluate quantitative joint space width (qJSW, at 10-, 30-, and 50-degree locations) in relation to incident radiographic and symptomatic hip osteoarthritis (rHOA and sxHOA, respectively) in a community-based cohort.

Methods: Data were from Johnston County OA Project (JoCoOA) participants with supine hip radiographs at each of 4 timepoints; all had Kellgren-Lawrence grades (KLG) and qJSW. We assessed covariates (age, race, height, weight, body mass index [BMI]) associated with qJSW, and hip-level associations between qJSW and HOA, over time using sex-stratified and multivariable-adjusted linear mixed models. A cluster analysis with logistic regression estimated associations between qJSW trajectory groups and incident rHOA and sxHOA.

Results: At baseline, 397 participants (784 hips, 41% men, 24% Black, mean age=57 years) had a mean BMI=29 kilograms/meter . Over a mean of 18 years, 20% and 12% developed incident KLG-defined rHOA or sxHOA, respectively. QJSW was more sensitive to changes over time at 50 degrees. Values were stable among men but declined over time in women. Heavier women lost more qJSW; changes in qJSW were not significantly associated with race, education, or injury in women or men. In women only, loss of qJSW over time was associated with 2-3 times higher odds of rHOA and sxHOA; among women and men, narrower baseline qJSW was associated with these outcomes.

Conclusion: Hip qJSW demonstrates marked sex differences, with significant loss over time only in women. Loss of qJSW over time in women, and narrower baseline qJSW in men and women, was associated with incident rHOA and sxHOA.
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http://dx.doi.org/10.1002/acr.24742DOI Listing
July 2021

Associations of Comorbid Conditions and Transitions Across States of Knee Osteoarthritis in a Community-Based Cohort.

ACR Open Rheumatol 2021 Jul 1. Epub 2021 Jul 1.

University of North Carolina at Chapel Hill.

Objective: To examine relationships between knee osteoarthritis (KOA) and obesity, diabetes mellitus (DM), and cardiovascular disease (CVD).

Methods: Associations of time-dependent obesity, DM, and CVD with KOA transition states over approximately 18 years were examined among 4093 participants from a community-based cohort. Transition states were 1) no knee symptoms and no radiographic KOA (rKOA; Kellgren-Lawrence grade ≥2 in at least one knee), 2) asymptomatic rKOA, 3) knee symptoms only, 4) symptomatic rKOA (sxKOA; rKOA and symptoms in same knee). Markov multistate models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for associations between comorbid conditions and transitions across states, adjusting for baseline age, sex, race, education, enrollment cohort, birth year, and time-dependent knee injury history.

Results: At baseline, 40% of participants had obesity, 13% had DM, and 22% had CVD (mean age = 61 years; 34% Black; 37% male). Compared with those without obesity, those with obesity had a higher hazard of worsening from no rKOA/no symptoms to asymptomatic rKOA (aHR = 1.7; 95% CI = 1.3-2.2) and from knee symptoms to sxKOA (aHR = 1.7; 95% CI = 1.3-2.3), as well as a lower hazard of symptom resolution from sxKOA to asymptomatic rKOA (aHR = 0.5 [95% = CI 0.4-0.7]). Compared with those without CVD, those with CVD had a higher hazard of worsening from no rKOA/symptoms to knee symptoms (aHR = 1.5; 95% CI = 1.1-2.1). DM was not associated with transitions of rKOA.

Conclusion: Prevention of obesity and CVD may limit the development or worsening of rKOA and symptoms.
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http://dx.doi.org/10.1002/acr2.11287DOI Listing
July 2021

Accelerometer-Based Physical Activity Patterns and Associations With Outcomes Among Individuals With Osteoarthritis.

J Clin Rheumatol 2021 Apr 24. Epub 2021 Apr 24.

From the Medical College of Georgia at Augusta University, Augusta, GA Department of Medicine and Thurston Arthritis Research Center Division of Physical Therapy and Thurston Arthritis Research Center, Injury Prevention Research Center, Department of Epidemiology Department of Nutrition Gillings School of Global Public Health and Center for Health Promotion and Disease Prevention, University of North Carolina, Chapel Hill, NC.

Background: This study examined patterns of physical activity and associations with pain, function, fatigue, and sleep disturbance among individuals with knee or hip osteoarthritis.

Methods: Participants (n = 54) were enrolled in a telephone-based physical activity coaching intervention trial; all data were collected at baseline. Self-reported measures of pain and function (WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index] subscales), fatigue (10-point numeric rating scale), and PROMIS (Patient-Reported Outcomes Information System) Sleep Disturbance were collected via telephone. Accelerometers were mailed to participants and were worn for at least 3 days. Proportion of time participants spent in sedentary behavior during the morning (from wake until 12:00 PM), afternoon (12:00 PM until 5:59 PM) and evening (6:00 PM until sleep) each day was averaged across all days of wear. Pearson correlations assessed associations between activity and self-reported measures.

Results: Participants spent a large proportion of time in sedentary behavior: 65.6% of mornings, 70.0% of afternoons, and 76.6% of evenings. Associations between proportion of time spent in sedentary behavior and reported outcomes were generally strongest in the afternoon, strongest for WOMAC function, and lowest for PROMIS Sleep Disturbance. In the evening hours, sedentary time was most strongly associated with fatigue.

Conclusions: Overall, findings stress the importance of reducing sedentary behavior among adults with osteoarthritis and suggest behavioral interventions may be strengthened by considering patients' within-day variation in symptoms and activity.
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http://dx.doi.org/10.1097/RHU.0000000000001750DOI Listing
April 2021

Discrimination Experiences and Depressive Symptoms among African Americans with Osteoarthritis Enrolled in a Pain Coping Skills Training Randomized Controlled Trial.

J Health Care Poor Underserved 2021 ;32(1):145-155

African Americans are more likely than members of other racial groups to report perceived discrimination in health care settings, and discrimination is linked to depression. Using data from a randomized controlled trial of pain coping skills training (PCST) for African Americans with osteoarthritis (N=164), we evaluated the interaction between discrimination experiences and experimental condition (PCST or control group) in linear regression models predicting depressive symptoms. There was a significant interaction between personal discrimination and experimental condition on depressive symptoms (interaction term coefficient: b=-3.2, 95% CI [- 6.4, - .02], p=.05). Discrimination was associated with depressive symptoms among those in the control group but not among those who received PCST. Participation in a PCST intervention may have reduced the association between discrimination experiences and depressive symptoms among participants in this sample. Future research should explore whether interventions aimed at teaching coping skills may be effective in ameliorating the harmful mental health effects of perceived discrimination.
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http://dx.doi.org/10.1353/hpu.2021.0014DOI Listing
January 2021

Application of Heterogeneity of Treatment Effect Methods: Exploratory Analyses of a Trial of Exercise-Based Interventions for Knee OA.

Arthritis Care Res (Hoboken) 2021 Jan 18. Epub 2021 Jan 18.

Center of Innovation to Accelerate Discovery and Practice Transformation, Durham VA Healthcare System, HSRD (152), 508 Fulton Street, Durham, NC, 27705, United States.

Objective: To evaluate heterogeneity of treatment effects (HTE) in a trial of exercise-based interventions for knee osteoarthritis (OA).

Methods: Participants (n=350) were randomized to standard physical therapy (PT; n=140), Internet-Based Exercise Training (IBET; n=142), or wait list control (WL; n=68). We applied QUalitative INteraction Trees (QUINT), a sequential partitioning method, and Generalized Unbiased Interaction Detection and Estimation (GUIDE), a regression tree approach, to identify subgroups with greater improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 4-months. Predictors included 24 demographic, clinical and psychosocial characteristics. We conducted internal validation to estimate optimism (bias) in the range of mean outcome differences among arms.

Results: Both QUINT and GUIDE indicated that for participants with lower body mass index (BMI), IBET was better than PT (improvements of WOMAC ranged from 6.3 to 9.1 points lower) and for those with higher BMI and longer duration of knee OA, PT was better than IBET (WOMAC improvement was 6.3 points). In GUIDE analyses comparing PT or IBET to WL, participants not employed had improvements in WOMAC ranging from 1.8 to 6.8 points lower with PT or IBT vs. WL. From internal validation, there were large corrections to the mean outcome differences among arms; however, after correction some differences remained in the clinically meaningful range.

Conclusion: Results suggest there may be subgroups who experience greater improvement in symptoms from PT or IBET, and this could guide referrals and future trials. However, uncertainty persists for specific treatment effect size estimates and how they apply beyond this study sample.
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http://dx.doi.org/10.1002/acr.24564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286274PMC
January 2021

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations.

J Bone Miner Res 2021 Mar 18;36(3):469-479. Epub 2020 Dec 18.

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10 ) and 7q31 (WNT16, p = 2.96 × 10 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10 ), 11q14 (DCDC5, p < 5.35 × 10 ), and 17p13 (SMG6, p < 6.78 × 10 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10 ), MBL2 (p = 4.09 × 10 ), MEPE (p = 3.15 × 10 ), SLC25A13 (p = 3.03 × 10 ), STARD3NL (p = 3.35 × 10 ), and TNFRSF11A (p = 3.18 × 10 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4220DOI Listing
March 2021

Acceptability of telephone-based pain coping skills training among African Americans with osteoarthritis enrolled in a randomized controlled trial: a mixed methods analysis.

BMC Musculoskelet Disord 2020 Aug 14;21(1):545. Epub 2020 Aug 14.

Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Background: Osteoarthritis (OA) disproportionately impacts African Americans compared to Caucasians, including greater pain severity. The Pain Coping Skills Training for African Americans with Osteoarthritis (STAART) study examined a culturally enhanced Pain Coping Skills Training (CST) program among African Americans with OA. This mixed methods study evaluated the acceptability of the Pain CST program among STAART participants.

Methods: STAART was a randomized controlled trial evaluating the effectiveness of an 11-session, telephone-based pain CST program, compared to a usual care control group. Participants were from the University of North Carolina and Durham Veterans Affairs Healthcare Systems. The present analyses included 93 participants in the CST group who completed a questionnaire about experiences with the program. Descriptive statistics of the questionnaire responses were calculated using SAS software. Thematic analysis was applied to open-response data using Dedoose software.

Results: Participants' mean rating of overall helpfulness of the pain CST program for managing arthritis symptoms was 8.0 (SD = 2.2) on a scale of 0-10. A majority of participants reported the program made a positive difference in their experience with arthritis (83.1%). Mean ratings of helpfulness of the specific skills ranged from 7.7 to 8.8 (all scales 0-10). Qualitative analysis of the open-response data identified four prominent themes: Improved Pain Coping, Mood and Emotional Benefits, Improved Physical Functioning, and experiences related to Intervention Delivery.

Conclusions: The high ratings of helpfulness demonstrate acceptability of this culturally enhanced pain CST program by African Americans with OA. Increasing access to cognitive-behavioral therapy-based programs may be a promising strategy to address racial disparities in OA-related pain and associated outcomes.

Trial Registration: NCT02560922 , registered September 25, 2015.
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http://dx.doi.org/10.1186/s12891-020-03578-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427940PMC
August 2020

Precision Medicine Approach to Develop and Internally Validate Optimal Exercise and Weight-Loss Treatments for Overweight and Obese Adults With Knee Osteoarthritis: Data From a Single-Center Randomized Trial.

Arthritis Care Res (Hoboken) 2021 05;73(5):693-701

University of North Carolina, Chapel Hill.

Objective: To apply a precision medicine approach to determine the optimal treatment regime for participants in an exercise (E), dietary weight loss (D), and D + E trial for knee osteoarthritis that would maximize their expected outcomes.

Methods: Using data from 343 participants of the Intensive Diet and Exercise for Arthritis (IDEA) trial, we applied 24 machine-learning models to develop individualized treatment rules on 7 outcomes: Short Form 36 physical component score, weight loss, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain/function/stiffness scores, compressive force, and interleukin-6 level. The optimal model was selected based on jackknife value function estimates that indicate improvement in the outcomes if future participants follow the estimated decision rule compared to the optimal single, fixed treatment model.

Results: Multiple outcome random forest was the optimal model for the WOMAC outcomes. For the other outcomes, list-based models were optimal. For example, the estimated optimal decision rule for weight loss indicated assigning the D + E intervention to participants with baseline weight not exceeding 109.35 kg and waist circumference above 90.25 cm, and assigning D to all other participants except those with a history of a heart attack. If applied to future participants, the optimal rule for weight loss is estimated to increase average weight loss to 11.2 kg at 18 months, contrasted with 9.8 kg if all participants received D + E (P = 0.01).

Conclusion: The precision medicine models supported the overall findings from IDEA that the D + E intervention was optimal for most participants, but there was evidence that a subgroup of participants would likely benefit more from diet alone for 2 outcomes.
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http://dx.doi.org/10.1002/acr.24179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483572PMC
May 2021

Genome-wide meta-analysis identified novel variant associated with hallux valgus in Caucasians.

J Foot Ankle Res 2020 Mar 4;13(1):11. Epub 2020 Mar 4.

University of Maryland School of Medicine, Baltimore, MD, USA.

Background: Hallux valgus, one of the most common structural foot deformities, is highly heritable. However, previous efforts to elucidate the genetic underpinnings of hallux valgus through a genome-wide association study (GWAS) conducted in 4409 Caucasians did not identify genome-wide significant associations with hallux valgus in both gender-specific and sex-combined GWAS meta-analyses. In this analysis, we add newly available data and more densely imputed genotypes to identify novel genetic variants associated with hallux valgus.

Methods: A total of 5925 individuals of European Ancestry were categorized into two groups: 'hallux valgus present' (n = 2314) or 'no deformity' (n = 3611) as determined by trained examiners or using the Manchester grading scale. Genotyping was performed using commercially available arrays followed by imputation to the Haplotype Reference Consortium (HRC) reference panel version 1.1. We conducted both sex-specific and sex-combined association analyses using logistic regression and generalized estimating equations as appropriate in each cohort. Results were then combined in a fixed-effects inverse-variance meta-analyses. Functional Mapping and Annotation web-based platform (FUMA) was used for positional mapping, gene and gene-set analyses.

Results: We identified a novel locus in the intronic region of CLCA2 on chromosome 1, rs55807512 (OR = 0.48, p = 2.96E-09), an expression quantitative trait locus for COL24A1, a member of the collagen gene family.

Conclusion: In this report of the largest GWAS of hallux valgus to date, we identified a novel genome-wide significant locus for hallux valgus. Additional replication and functional follow-up will be needed to determine the functional role of this locus in hallux valgus biology.
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http://dx.doi.org/10.1186/s13047-020-0379-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057609PMC
March 2020

Racial Differences in Performance-Based Function and Potential Explanatory Factors Among Individuals With Knee Osteoarthritis.

Arthritis Care Res (Hoboken) 2020 09;72(9):1196-1204

University of North Carolina at Chapel Hill and Durham VA Medical Center, Durham, North Carolina.

Objective: In individuals with knee osteoarthritis (OA), self-reported physical function is poorer in African Americans than in whites, but whether this difference holds true for objective assessments is unclear. The purpose of this study was to examine racial differences in performance-based physical function as well as potential underlying factors contributing to these racial differences.

Methods: Participants with knee OA from a randomized controlled trial completed the 2-minute step test (2MST), timed-up-and-go (TUG), and 30-second chair stand (30s-CST) at baseline. Race differences in performance-based function were assessed by logistic regression. Separate models were adjusted for sets of demographic, socioeconomic, psychological health, and physical health variables.

Results: In individuals with knee OA (n = 322; 72% women, 22% African American, mean ± SD age 66 ± 11 years, mean ± SD body mass index 31 ± 8 kg/m ), African Americans (versus whites) had greater unadjusted odds of poorer function (30s-CST odds ratio [OR] 2.79 [95% confidence interval (95% CI) 1.65-4.72], 2MST OR 2.37 [95% CI 1.40-4.03], and TUG OR 3.71 [95% CI 2.16-6.36]). Relationships were maintained when adjusted for demographic and psychological health covariates, but they were either partially attenuated or nonsignificant when adjusted for physical health and socioeconomic covariates.

Conclusion: African American adults with knee OA had poorer unadjusted performance-based function than whites. Physical health and socioeconomic characteristics diminished these differences, emphasizing the fact that these factors may be important to consider in mitigating racial disparities in function.
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http://dx.doi.org/10.1002/acr.24018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935430PMC
September 2020

Pain coping skills training for African Americans with osteoarthritis: results of a randomized controlled trial.

Pain 2019 06;160(6):1297-1307

Department of Psychiatry and Behavioral Science, Duke University, Durham, NC, United States.

African Americans bear a disproportionate burden of osteoarthritis (OA), but they have been underrepresented in trials of behavioral interventions for pain. This trial examined a culturally tailored pain coping skills training (CST) program, compared to a wait list control group, among 248 African Americans with knee or hip OA. The pain CST program involved 11 telephone-based sessions over 3 months. Outcomes were assessed at baseline, 3 months (primary), and 9 months, and included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (primary outcome), WOMAC total score and function subscale, PROMIS Pain Interference, Short-Form 12 Mental and Physical Composite Subscales, Coping Strategies Questionnaire-Total Coping Attempts, Pain Catastrophizing Scale, Patient Health Questionnaire-8, Arthritis Self-Efficacy Scale, and Patient Global Impression of Arthritis Symptom Change. Linear mixed models were fit for all outcomes. There were no significant between-group differences in WOMAC pain score at 3 months (-0.63 [95% confidence interval -1.45, 0.18]; P = 0.128) or 9 months (-0.84 [95% confidence interval -1.73, 0.06]; P = 0.068). Among secondary outcomes, at 3 months, there were significant differences, in favor of the CST group, for Coping Strategies Questionnaire Total Coping Attempts, Pain Catastrophizing Scale, Arthritis Self-Efficacy, and Patient Global Impression of Arthritis Symptom Change (P < 0.01). Coping Strategies Questionnaire Total Coping Attempts, Arthritis Self-Efficacy, and Patient Global Assessment Change were also significantly improved at 9 months in the CST group, compared with wait list (P < 0.01). The culturally tailored pain CST program did not significantly reduce pain severity but did improve key measures of pain coping and perceived ability to manage pain among African Americans with OA.
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http://dx.doi.org/10.1097/j.pain.0000000000001525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719680PMC
June 2019

Application of Traditional and Emerging Methods for the Joint Analysis of Repeated Measurements With Time-to-Event Outcomes in Rheumatology.

Arthritis Care Res (Hoboken) 2020 05 8;72(5):615-621. Epub 2020 Apr 8.

University of North Carolina, Chapel Hill.

Objective: The goal of this paper is to describe approaches for the joint analysis of repeatedly measured data with time-to-event end points, first separately and then in the framework of a single comprehensive model, emphasizing the efficiency of the latter approach. Data from the Johnston County Osteoarthritis (JoCo OA) Project will be used as an example to investigate the relationship between the change in repeatedly measured body mass index (BMI) and the time-to-event end point of incident worsening of radiographic knee OA that was defined as an increased Kellgren/Lawrence grade in at least 1 knee over time.

Methods: First, we provide an overview of the methods for analyzing repeated measurements and time-to-event end points separately. Then, we describe traditional (Cox proportional hazards model [CoxPH]) and emerging (joint model [JM]) approaches, both of which allow combined analysis of repeated measures with a time-to-event end point in the framework of a single statistical model. Finally, we apply the models to JoCo OA data and interpret and compare the results from the different approaches.

Results: Applications of the JM (but not the CoxPH) showed that the risk of worsening radiographic OA is higher when BMI is higher or increasing, thus illustrating the advantages of the JM for analyzing such dynamic measures in a longitudinal study.

Conclusion: Joint models are preferable for simultaneous analyses of repeated measurement and time-to-event outcomes, particularly in the context of chronic disease, where dependency between the time-to-event end point and the longitudinal trajectory of repeated measurements is inherent.
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http://dx.doi.org/10.1002/acr.23881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761043PMC
May 2020

Fall Risk and Utilization of Balance Training for Adults With Symptomatic Knee Osteoarthritis: Secondary Analysis From a Randomized Clinical Trial.

J Geriatr Phys Ther 2019 Apr/Jun;42(2):E39-E44

Division of Physical Therapy, Department of Allied Health Sciences, University of North Carolina at Chapel Hill.

Background And Purpose: Knee osteoarthritis (KOA) is a common disease that hinders activity participation in older adults. Associated symptoms and physiological changes can increase risk of falling in individuals with KOA. Balance training can decrease fall risks in older adults. Limited evidence exists regarding utilization of balance training in physical therapy (PT) for this population. This secondary data analysis investigated the proportion of participants at high risk for falling in the PhysicAl THerapy vs. INternet-based Exercise Training for Patients with Osteoarthritis (PATH-IN) study and the frequency with which balance training was utilized as an intervention in PT.

Methods: PATH-IN study participants (N = 344) performed the Four-Stage Balance Test and the Timed Up and Go (TUG) test during baseline assessment. Participants were randomly allocated to PT, an Internet-based exercise program, or a control group. Participants were classified as being at high risk for falling if they did not progress to the single-leg stance (SLS) during the Four-Stage Balance Test, were unable to maintain SLS for 5 seconds, or took longer than 13.5 seconds to complete the TUG test. The proportion of participants at high risk for falling was calculated for all participants and separately for those allocated to PT. In addition, PT notes were coded for balance training and the frequency of balance training utilization was calculated.

Results And Discussion: Upon enrollment, 35.5% (N = 122) of all participants and 36.2% (N = 50) of those allocated to PT were at high risk for falling. Of participants allocated to PT with documentation available for coding (N = 118), 35.5% (N = 42) were at high risk for falling. Balance training was provided to 62.7% (N = 74) during at least one PT session. Of those classified as being at high risk for falling, 33.3% (N = 14) did not receive balance training.

Conclusions: The finding of high fall risks in more than one-third of all participants with KOA is consistent with previous reports of a higher risk of falling in this population. Many PT participants did receive some balance training; however, one-third of participants at high risk for falling did not. Balance training for individuals with KOA at high risk for falling may be underutilized.
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http://dx.doi.org/10.1519/JPT.0000000000000213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422722PMC
March 2020

How Well Does the Family Longevity Selection Score Work: A Validation Test Using the Utah Population Database.

Front Public Health 2018 1;6:277. Epub 2018 Oct 1.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United States.

The Family Longevity Selection Score (FLoSS) was used to select families for the Long Life Family Study (LLFS) but has never been validated in other populations. The goal of this paper is to validate how well the FLoSS-based selection procedure works in an independent dataset. In this paper, we computed FLoSS using the lifespan data of 234,155 individuals from a large comprehensive genealogically-based resource, the Utah Population Database (UPDB), born between 1779 and 1910 with mortality follow-up through 2012-2013. Computations of FLoSS in a specific year (1980) confirmed the survival advantage of the "exceptional" sibships (defined by LLFS FLoSS threshold, FLoSS ≥ 7). We found that the subsample of the UPDB participants born after 1900 who were from the "exceptional" sibships had survival curves similar to that of the US participants from the LLFS probands' generation. Comparisons between the offspring of parents with "exceptional" and "ordinary" survival showed the survival advantage of the "exceptional" offspring. Investigators seeking to explain the extent genetics and environment contribute to exceptional survival will benefit from the use of exceptionally long-lived individuals and their relatives. Appropriate ranking of families by survival exceptionality and their availability for the purposes of providing genetic and phenotypic data is critical for selecting participants into such studies. This study validated the FLoSS as selection criteria in family longevity studies using UPDB.
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http://dx.doi.org/10.3389/fpubh.2018.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174319PMC
October 2018

Genetics of Human Longevity From Incomplete Data: New Findings From the Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2018 10;73(11):1472-1481

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina.

The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.
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http://dx.doi.org/10.1093/gerona/gly057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175028PMC
October 2018

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

PLoS Genet 2018 09 27;14(9):e1007601. Epub 2018 Sep 27.

Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
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http://dx.doi.org/10.1371/journal.pgen.1007601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159857PMC
September 2018

Pain coping skills training for African Americans with osteoarthritis study: baseline participant characteristics and comparison to prior studies.

BMC Musculoskelet Disord 2018 Sep 19;19(1):337. Epub 2018 Sep 19.

Department of Psychology, East Carolina University, Greenville, NC, USA.

Background: The Pain Coping Skills Training for African Americans with OsteoaRTthritis (STAART) trial is examining the effectiveness of a culturally enhanced pain coping skills training (CST) program for African Americans with osteoarthritis (OA). This disparities-focused trial aimed to reach a population with greater symptom severity and risk factors for poor pain-related outcomes than previous studies. This paper compares characteristics of STAART participants with prior studies of CST or cognitive behavioral therapy (CBT)-informed training in pain coping strategies for OA.

Methods: A literature search identified 10 prior trials of pain CST or CBT-informed pain coping training among individuals with OA. We descriptively compared characteristics of STAART participants with other studies, in 3 domains of the National Institutes of Minority Health and Health Disparities' Research Framework: Sociocultural Environment (e.g., age, education, marital status), Biological Vulnerability and Mechanisms (e.g, pain and function, body mass index), and Health Behaviors and Coping (e.g., pain catastrophizing). Means and standard deviations (SDs) or proportions were calculated for STAART participants and extracted from published manuscripts for comparator studies.

Results: The mean age of STAART participants, 59 years (SD = 10.3), was lower than 9 of 10 comparator studies; the proportion of individuals with some education beyond high school, 75%, was comparable to comparator studies (61-86%); and the proportion of individuals who are married or living with a partner, 42%, was lower than comparator studies (62-66%). Comparator studies had less than about 1/3 African American participants. Mean scores on the Western Ontario and McMaster Universities Osteoarthritis Index pain and function scales were higher (worse) for STAART participants than for other studies, and mean body mass index of STAART participants, 35.2 kg/m (SD = 8.2), was higher than all other studies (30-34 kg/m). STAART participants' mean score on the Pain Catastrophizing scale, 19.8 (SD = 12.3), was higher (worse) than other studies reporting this measure (7-17).

Conclusions: Compared with prior studies with predominantly white samples, STAART participants have worse pain and function and more risk factors for negative pain-related outcomes across several domains. Given STAART participants' high mean pain catastrophizing scores, this sample may particularly benefit from the CST intervention approach.

Trial Registration: NCT02560922.
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http://dx.doi.org/10.1186/s12891-018-2249-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145122PMC
September 2018

Level of participation in physical therapy or an internet-based exercise training program: associations with outcomes for patients with knee osteoarthritis.

BMC Musculoskelet Disord 2018 Jul 19;19(1):238. Epub 2018 Jul 19.

Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Thurston Bldg., CB#, Chapel Hill, NC, 7280, USA.

Background: To examine whether number of physical therapy (PT) visits or amount of use of an internet-based exercise training (IBET) program is associated with differential improvement in outcomes for participants with knee osteoarthritis (OA).

Methods: A secondary analysis was performed using data from participants in 2 arms of a randomized control trial for individuals with symptomatic knee OA: PT (N = 135) or IBET (N = 124). We examined associations of number of PT visits attended (up to 8) or number of days the IBET website was accessed during the initial 4-month study period with changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, pain and function subscales, as well as a 2-min Step Test, at 4-month and 12-month follow-up.

Results: Participants with more PT visits experienced greater improvement in WOMAC total score (estimate per additional visit = - 1.18, CI 95% = - 1.91, 0.46, p <  0.001) and function subscore (estimate = - 0.80, CI 95% = - 1.33, - 0.28, p <  0.001) across follow-up periods. For WOMAC pain subscale, the association with number of PT visits varied significantly between 4- and 12-month follow-up, with a stronger relationship at 4-months. There was a non-significant trend for more PT visits to be associated with greater improvement in 2-min Step Test. More frequent use of the IBET website was not associated with greater improvement for any outcome, at either time point.

Conclusion: Increased number of PT visits was associated with improved outcomes, and some of this benefit persisted 8 months after PT ended. This provides guidance for PT clinical practice and policies.

Trial Registration: NCT02312713 , posted 9/25/2015.
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http://dx.doi.org/10.1186/s12891-018-2139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053740PMC
July 2018

Demographic and Clinical Factors Associated With Nonsurgical Osteoarthritis Treatment Among Patients in Outpatient Clinics.

Arthritis Care Res (Hoboken) 2018 08 5;70(8):1141-1149. Epub 2018 Jul 5.

Veterans Affairs Medical Center, Durham, and University of North Carolina, Chapel Hill.

Objective: To identify patient demographic and clinical characteristics associated with osteoarthritis (OA) treatment use.

Methods: This was a secondary data analysis of 3 clinical trials among patients with hip or knee OA conducted in Duke Primary Care practices, the Durham Veterans Affairs (VA) Health Care System, and the University of North Carolina-Chapel Hill (UNC). At baseline, participants reported sociodemographic characteristics, OA-related pain and function, and OA treatment use, including oral analgesics, topical creams, joint injections, and physical therapy. Separate, multivariable logistic models (adjusted for clustering of clinics and providers for the Duke and VA cohorts) were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between participant characteristics and each type of OA treatment.

Results: Oral analgesic use was reported by 70-82% of participants across the 3 cohorts. Physical therapy, knee injections, and topical creams were used by 39-52%, 55-60%, and 25-39% of Duke, VA, and UNC participants, respectively. In multivariable models, worse pain, stiffness, and function, per 5-unit increase, were associated with greater odds of using any oral analgesic for the cohorts from Duke (OR 1.18 [95% CI 1.08-1.28]) and UNC (OR 1.14 [95% CI 1.05-1.24]), but not for the VA cohort (OR 1.04 [95% CI 0.95-1.14]). For all 3 cohorts, nonwhites had higher odds of using topical creams compared to whites.

Conclusion: Results suggest potential underutilization of therapies other than oral analgesics. Patient characteristics may affect OA treatment use, and understanding the relationship between these factors and OA treatment preferences may improve adherence to OA treatment guidelines.
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http://dx.doi.org/10.1002/acr.23466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945338PMC
August 2018

Randomized Controlled Trial of a Home-Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor-Associated Arthralgia in Breast Cancer Survivors.

Oncologist 2017 10 11;22(10):1238-1249. Epub 2017 Jul 11.

Division of Hematology-Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: In postmenopausal women diagnosed with breast cancer (BC), most BC tumors are hormone receptor positive and guidelines recommend adjuvant endocrine therapy that includes an aromatase inhibitor (AI). This study investigates the impact of a 6-week, home-based, self-directed walking program on the commonly reported side effect of AI-associated arthralgia (AIAA).

Materials And Methods: In this phase II trial, consented BC patients were randomized to walking Intervention ( = 31) or Wait List Control (WLC;  = 31). Eligibility criteria included: stage 0-III BC, on AI for at least 4 weeks, ≥3 on a 5-point scale inquiring about joint symptom intensity "at its worst," and exercising ≤150 minutes per week. Outcomes were self-reported joint symptoms and psychosocial measures. Analyses comparing Intervention and WLC groups were conducted on an intention-to-treat basis to assess intervention impact at 6 weeks (postintervention) and at 6-months follow-up. Adjusted means were calculated to assess differences in two groups.

Results: In our final sample ( = 62), mean age was 64 years, 74% were white, and 63% had a body mass index of 30 or higher. At postintervention, Intervention group participants reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living (ADL), and less perceived helplessness in managing joint symptoms. At 6-months follow-up (postwalking period in both Intervention and WLC), walking minutes per week had decreased significantly; however, improvements in stiffness and difficulty with ADLs were maintained.

Conclusion: This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.

Implications For Practice: Breast cancer survivors whose adjuvant endocrine treatment includes an aromatase inhibitor (AI) often experience the side effect of AI-associated arthralgia (AIAA). This study investigates the impact of a 6-week, home-based, self-directed walking program in the management of AIAA. Compared with Wait List Control, women in the Intervention group reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living, and less perceived helplessness in managing joint symptoms. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.
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http://dx.doi.org/10.1634/theoncologist.2017-0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634775PMC
October 2017

Fear of Movement and Associated Factors Among Adults With Symptomatic Knee Osteoarthritis.

Arthritis Care Res (Hoboken) 2017 Dec 6;69(12):1826-1833. Epub 2017 Nov 6.

University of North Carolina, Chapel Hill, and Center for Health Services Research in Primary Care, Durham VA Medical Center, Durham, North Carolina.

Objective: To examine the frequency of and factors associated with fear of movement (FOM) among patients with symptomatic knee osteoarthritis (KOA), using the new Brief Fear of Movement (BFOM) measure.

Methods: Participants (n = 350) enrolled in a clinical trial completed the BFOM scale prior to randomization. The relationships of BFOM with the following characteristics were examined: age, sex, race, education, pain and activities of daily living (ADL) subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS), knee symptom duration, depressive symptoms (8-item Patient Health Questionnaire [PHQ-8]), history of falls and knee injury, family history of knee problems, self-efficacy for exercise (SEE), and unilateral balance test. A proportional odds logistic regression model examined multivariable associations of participant characteristics with a 3-level BFOM variable (agreement with 0, 1-2, or ≥3 items).

Results: The majority of participants (77%) agreed with at least 1 item on the BFOM scale, and 36% endorsed 3+ items, suggesting a high degree of FOM. In the multivariable model, the following remained significant after backward selection: age (odds ratio [OR] 0.79 per 10-point increase, 95% confidence interval [95% CI] 0.66-0.95), KOOS ADL (OR 0.86 per 10-point increase, 95% CI 0.76-0.97), PHQ-8 (OR 1.15, 95% CI 1.08-1.22), and SEE (OR 0.87 per 10-point increase, 95% CI 0.78-0.96).

Conclusion: FOM was common among patients with symptomatic KOA, and this could negatively impact physical activity. Psychological variables were significantly associated with FOM, suggesting behavioral and psychological interventions may decrease FOM and improve outcomes among individuals with symptomatic KOA.
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http://dx.doi.org/10.1002/acr.23226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020682PMC
December 2017

Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.

Front Genet 2016 8;7:188. Epub 2016 Nov 8.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.

This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.
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http://dx.doi.org/10.3389/fgene.2016.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099244PMC
November 2016

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

PLoS Genet 2016 Nov 10;12(11):e1006314. Epub 2016 Nov 10.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.
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http://dx.doi.org/10.1371/journal.pgen.1006314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104356PMC
November 2016

How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data.

N Am Actuar J 2016 22;20(3):201-232. Epub 2016 Jun 22.

Sr. Research Scientist, Center for Population Health and Aging, Duke University, 2024 W. Main Street, Room A105, Durham, NC 27705, USA. Tel.: (+1) 919-668-2712.

Background And Objective: To clarify mechanisms of genetic regulation of human aging and longevity traits, a number of genome-wide association studies (GWAS) of these traits have been performed. However, the results of these analyses did not meet expectations of the researchers. Most detected genetic associations have not reached a genome-wide level of statistical significance, and suffered from the lack of replication in the studies of independent populations. The reasons for slow progress in this research area include low efficiency of statistical methods used in data analyses, genetic heterogeneity of aging and longevity related traits, possibility of pleiotropic (e.g., age dependent) effects of genetic variants on such traits, underestimation of the effects of (i) mortality selection in genetically heterogeneous cohorts, (ii) external factors and differences in genetic backgrounds of individuals in the populations under study, the weakness of conceptual biological framework that does not fully account for above mentioned factors. One more limitation of conducted studies is that they did not fully realize the potential of longitudinal data that allow for evaluating how genetic influences on life span are mediated by physiological variables and other biomarkers during the life course. The objective of this paper is to address these issues.

Data And Methods: We performed GWAS of human life span using different subsets of data from the original Framingham Heart Study cohort corresponding to different quality control (QC) procedures and used one subset of selected genetic variants for further analyses. We used simulation study to show that approach to combining data improves the quality of GWAS. We used FHS longitudinal data to compare average age trajectories of physiological variables in carriers and non-carriers of selected genetic variants. We used stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways.

Results: We showed that the use of different QC procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span. We showed that the joint analyses of genetic data at the time of bio-specimen collection and follow up data substantially improved significance of associations of selected 24 SNPs with life span. We also showed that aging related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and non-carriers of selected variants.

Conclusions: . The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070546PMC
http://dx.doi.org/10.1080/10920277.2016.1178588DOI Listing
June 2016

Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.

Aging Cell 2017 Feb 28;16(1):61-72. Epub 2016 Sep 28.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.

Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age-related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age-related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high-density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large-scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10 for rs693 and β = -1.08, P = 9.8 × 10 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects-protecting against MI risks (β = -0.18, P = 1.1 × 10 ) or increasing MI risks (β = 0.15, P = 2.8 × 10 ) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10 ) that is contrasted with a weak estimate following the traditional, sample-size-centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.
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http://dx.doi.org/10.1111/acel.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242299PMC
February 2017

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study.

Biogerontology 2016 11 22;17(5-6):893-905. Epub 2016 Jul 22.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.

The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (β = -7.1, p = 6.6 × 10). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065761PMC
http://dx.doi.org/10.1007/s10522-016-9659-3DOI Listing
November 2016

Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk.

Front Public Health 2016 25;4. Epub 2016 Jan 25.

Biodemography of Aging Research Unit (BARU), Social Science Research Institute, Duke University , Durham, NC , USA.

While longitudinal changes in biomarker levels and their impact on health have been characterized for individual markers, little is known about how overall marker profiles may change during aging and affect mortality risk. We implemented the recently developed measure of physiological dysregulation based on the statistical distance of biomarker profiles in the framework of the stochastic process model of aging, using data on blood pressure, heart rate, cholesterol, glucose, hematocrit, body mass index, and mortality in the Framingham original cohort. This allowed us to evaluate how physiological dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We found that physiological dysregulation increases with age; that increased dysregulation is associated with increased mortality, and increasingly so with age; and that, in most but not all cases, there is a decreasing ability to return quickly to baseline physiological state with age. We also revealed substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk.
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http://dx.doi.org/10.3389/fpubh.2016.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725219PMC
February 2016

Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.

PLoS One 2015 21;10(8):e0136319. Epub 2015 Aug 21.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, United States of America.

Insights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136319PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546650PMC
May 2016

How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.

Biogerontology 2016 Feb 18;17(1):89-107. Epub 2015 Aug 18.

The Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, USA.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.
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http://dx.doi.org/10.1007/s10522-015-9594-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724574PMC
February 2016
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