Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Clinical and imaging findings associated with preservation of knee joint health over 8 years in individuals aged 65 and over: data from the OAI.

OBJECTIVE: While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. METHODS: This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. RESULTS: Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. CONCLUSION: Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

Effect of weight loss on knee joint synovitis over 48 months and mediation by subcutaneous fat around the knee: data from the Osteoarthritis Initiative.

BACKGROUND: Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. METHODS: We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (< ± 3% change, n = 117) over 48 months matched for age and sex. In magnetic resonance imaging (MRI) at baseline and 48 months, effusion-synovitis and Hoffa-synovitis using the MRI Osteoarthritis Knee Score (MOAKS) and average joint-adjacent SCF (ajSCF) were assessed. Odds-ratios (ORs) for synovitis progression over 48 months (≥ 1 score increase) were calculated in logistic regression models adjusting for age, sex, baseline BMI, Physical Activity Scale for the Elderly (PASE), and baseline SCF measurements. Mediation of the effect of weight loss on synovitis progression by local SCF change was assessed. RESULTS: Odds for effusion-synovitis progression decreased with weight loss and ajSCF decrease (odds ratio [OR] = 0.61 and 0.56 per standard deviation [SD] change, 95% confidence interval [CI] 0.44, 0.83 and 0.40, 0.79, p = 0.002 and 0.001, respectively), whereas odds for Hoffa-synovitis progression increased with weight loss and ajSCF decrease (OR = 1.47 and 1.48, CI 1.05, 2.04 and 1.02, 2.13, p = 0.024 and 0.038, respectively). AjSCF decrease mediated 39% of the effect of weight loss on effusion-synovitis progression. CONCLUSIONS: Effusion-synovitis progression was slowed by weight loss and decrease in local subcutaneous fat. Hoffa-synovitis characterized by fluid in the infrapatellar fat pad increased at the same time, suggesting a decreasing fat pad rather than active synovitis. Decrease in local subcutaneous fat partially mediated the systemic effect of weight loss on synovitis.

Thigh muscle and fat volumes are associated with knee cartilage abnormalities and bone marrow edema-like lesions: data from the osteoarthritis initiative.

OBJECTIVE: To investigate the associations of thigh muscle and fat volumes with structural abnormalities on MRI related to knee osteoarthritis. MATERIALS AND METHODS: MRI studies of the thighs and knees from 100 individuals were randomly selected from the Osteoarthritis Initiative Cohort. Whole Organ MR Scoring (WORMS) and effusion-synovitis scoring were performed in all knee MRI. Thigh muscles, intermuscular fat, and subcutaneous fat were manually segmented in 15 consecutive MR thigh images. Radiographic Kellgren-Lawrence grades (KLG) were also obtained in all knee radiographs. Independent t-tests were used to investigate the associations between thigh muscle and fat volumes, and sex. Mixed-effects analyses were obtained to investigate the associations between thigh muscle and fat volumes, KLG, WOMAC pain score, cartilage and bone marrow WORMS, as well as effusion-synovitis scores. RESULTS: Women had higher subcutaneous fat volume than men (616.82 vs. 229.13 cm3, p < 0.01) and men had higher muscle volumes than women (p < 0.01). Quadriceps (coef = -2.15, p = 0.01) and vastus medialis (coef = -1.84, p = 0.03) volumes were negatively associated with the WORMS cartilage scores. Intermuscular fat volume (coef = 0.48, p = 0.01) was positively associated with WORMS bone marrow edema-like lesion (BMEL) scores. The quadriceps (coef = -0.99, p < 0.01) and hamstring (coef = -0.59, p = 0.01) volumes were negatively associated with WORMS BMEL scores. No evidence of an association was found between thigh muscle and fat volumes with KLG and effusion-synovitis grading (p > 0.05). CONCLUSION: Increased quadriceps and hamstring volumes were negatively associated with cartilage lesion and BMEL scores while no evidence of an association was found between thigh muscle and fat volumes, and radiographic knee osteoarthritis or effusion-synovitis grading.

Analogies in Genomics Policymaking: Debates and Drawbacks.

The analogy between genomics and imaging has been an important touchstone in the debate on how secondary findings should be handled in both clinical and research genomics contexts. However, a critical eye is needed to understand whether an analogy like this one provides an adequate basis for policymaking in genomics. Genomics and imaging are undoubtedly similar in certain ways, but whether that similarity is adequate to justify adopting identical policies is a task that requires further analysis. This is highlighted by the fact that secondary findings are produced in other domains of medicine and public health, such as newborn screening programs, routine laboratory panels, and antibiotic sensitivity testing, and that the practices for handling secondary findings in each of these areas are different. These examples demonstrate that medicine has no single comprehensive policy or set of practices for managing secondary findings. Analogies to imaging, newborn screening, routine testing panels, and antibiotic sensitivity testing all lead to different policy options for genomics. In this piece we argue that analogies are a powerful way of driving policy discussions by rendering two different areas of medical practice similar, but an overdependence on a single analogy risks limiting policy discussions in potentially deleterious ways.

Associations between weight change, knee subcutaneous fat and cartilage thickness in overweight and obese individuals: 4-Year data from the osteoarthritis initiative.

OBJECTIVE: To assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness. DESIGN: Individuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)). RESULTS: Individuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p < 0.001) than controls; individuals who gained weight had significantly greater joint-adjacent SCF than controls (beta range: -1.4 to -3.9 mm, p < 0.001). No statistically significant associations were found between weight change and cartilage thickness change. However, increases in joint-adjacent SCF over 4 years were significantly associated with decreases in cartilage thickness (p = 0.04). CONCLUSIONS: Weight change was associated with joint-adjacent SCF, but not with change in cartilage thickness. However, 4-year increases in joint-adjacent SCF were associated with decreases in cartilage thickness independent of baseline BMI and weight change group.

Revising the Bioethics Story: Memory and Story in Precarious Times.

The foundation story of bioethics is, as Susan Reverby (2009) argues, one of a trinity of horror stories culminating in what we commonly call the "Tuskegee Syphilis Study." The foundation story emphasizes that medical researchers violated participant autonomy by deceiving them about their medical conditions, the goals of the study, and the treatments they would receive, and by failing to consider the health and best interests of the research participant. While this story reflects some key elements of the Tuskegee study, it is only a selection of all the possible facts that, as a consequence, deflects attention from equally salient and problematic elements of the Public Health Service's unethical study and its context. Those elements not included in the bioethics foundation story represent the types of racial and social inequities that COVID-19 and other contemporary events have thrown into stark relief. If bioethics plans to emphasize translational work around public policy and public engagement understood broadly, then it will need to revise and expand the story it tells about itself and its founding.

Quantitative Three-dimensional Assessment of Knee Joint Space Width from Weight-bearing CT.

Background Imaging of structural disease in osteoarthritis has traditionally relied on MRI and radiography. Joint space mapping (JSM) can be used to quantitatively map joint space width (JSW) in three dimensions from CT images. Purpose To demonstrate the reproducibility, repeatability, and feasibility of JSM of the knee using weight-bearing CT images. Materials and Methods Two convenience samples of weight-bearing CT images of left and right knees with radiographic Kellgren-Lawrence grades (KLGs) less than or equal to 2 were acquired from 2014 to 2018 and were analyzed retrospectively with JSM to deliver three-dimensional JSW maps. For reproducibility, images of three sets of knees were used for novice training, and then the JSM output was compared against an expert's assessment. JSM was also performed on 2-week follow-up images in the second cohort, yielding three-dimensional JSW difference maps for repeatability. Statistical parametric mapping was performed on all knee imaging data (KLG, 0-4) to show the feasibility of a surface-based analysis in three dimensions. Results Reproducibility (in 20 individuals; mean age, 58 years ± 7 [standard deviation]; mean body mass index, 28 kg/m2 ± 6; 14 women) and repeatability (in nine individuals; mean age, 53 years ± 6; mean body mass index, 26 kg/m2 ± 4; seven women) reached their lowest performance at a smallest detectable difference less than ±0.1 mm in the central medial tibiofemoral joint space for individuals without radiographically demonstrated disease. The average root mean square coefficient of variation was less than 5% across all groups. Statistical parametric mapping (33 individuals; mean age, 57 years ± 7; mean body mass index, 27 kg/m2 ± 6; 23 women) showed that the central-to-posterior medial joint space was significantly narrower by 0.5 mm for each incremental increase in the KLG (threshold P < .05). One knee (KLG, 2) demonstrated a baseline versus 24-month change in its three-dimensional JSW distribution that was beyond the smallest detectable difference across the lateral joint space. Conclusion Joint space mapping of the knee using weight-bearing CT images is feasible, demonstrating a relationship between the three-dimensional joint space width distribution and structural joint disease. It is reliably learned by novice users, can be personalized for disease phenotypes, and can be used to achieve a smallest detectable difference that is at least 50% smaller than that reported to be achieved at the highest performance level in radiography. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Roemer in this issue.

Indicator Dyes and Catalytic Nanoparticles for Irreversible Visual Hydrogen Sensing.

Using ultraviolet-visible (UV-vis) absorption spectroscopy, we have tested the reactivity of various indicator molecules combined with catalytic bimetallic gold-palladium nanoparticles (Au-Pd NPs) in solution for an irreversible and visual response to H2. Our aim was to identify the most suitable indicator/Au-Pd NP system for the future development of a thin, wearable, and visual H2 sensor for noninvasive monitoring of in vivo Mg-implant biodegradation in research and clinical settings with fast response time. The indicators studied were bromothymol blue, methyl red, and resazurin, and the reactions of each system with H2 in the presence of Au-Pd NPs caused visual and irreversible color changes that were concluded to proceed via redox processes. The resazurin/Au-Pd NP system was deemed best-suited for our research objectives because (1) this system had the fastest color change response to H2 at levels relevant to in vivo Mg-implant biodegradation compared to the other indicator/Au-Pd NP systems tested, (2) the observed redox chemistry with H2 followed well-understood reaction pathways reported in the literature, and (3) the redox products were nontoxic and appropriate for medical applications. Studying the effects of the concentrations of H2, Au-Pd NPs, and resazurin on the color change response time within the resazurin/Au-Pd NP system revealed that the H2-sensing elements can be optimized to achieve a faster or slower color change with H2 by varying the relative amounts of resazurin and Au-Pd NPs in solution. The results from this study are significant for future optical H2 sensor design.

Natural history of new horizontal meniscal tears in individuals at risk for and with mild to moderate osteoarthritis: data from osteoarthritis initiative.

OBJECTIVES: To study the natural history of new horizontal meniscal tears and their association with progression of cartilage degeneration in individuals at risk for or with mild to moderate knee osteoarthritis over 4 years. METHODS: Individuals who developed a new meniscal tear in the right knee over 2 years were selected from the Osteoarthritis Initiative 3T MRI studies. Knee structural changes were analyzed at the time of tear appearance (baseline), and after 4 years using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Meniscal tears were classified as either horizontal tears or non-horizontal tears. Individuals without a meniscal tear were 1:3 frequency matched according to BMI, gender, race, and age and served as the control group. Linear regression analysis was used to compare cross-sectional and longitudinal changes in cartilage WORMS scores. RESULTS: Forty-one subjects developed horizontal tears, including one indiviudal who developed a tear in both menisci, and 34 developed non-horizonal tears. We found that (29/41 (70.7%)) of horizontal and (20/34 (58.8%)) of non-horizonatal tears were stable during follow-up (p = 0.281). Although knees with an incident tear had higher than controls WORMS MAX total knee scores at baseline (coef. = 0.47, p = 0.044, 95% CI = 0.01 to 0.93), there were no significant differences between the horizontal subgroup and knees without tears in overall cartilage scores at baseline and in progression over 4 years of follow-up. CONCLUSIONS: New horizontal meniscal tears tended to be stable over 4 years and presented no significant differences in progression of cartilage degeneration when compared with knees without tears. KEY POINTS: • Most of horizonal meniscal tears were stable over 4 years. • There were no statistically significant differences in overall progression of cartilage degenerative changes between knees with horizonal meniscal tears and control knees without tears • Horizontal tears most often occurred at the posterior horn of the medial meniscus and at the body of the lateral meniscus.

Patterns of Change Over Time in Knee Bone Shape Are Associated with Sex.

BACKGROUND: Knee osteoarthritis (OA) is more common in females than in males; however, the biological mechanisms for the difference in sex in patients with knee OA are not well understood. Knee shape is associated with OA and with sex, but the patterns of change in the bone's shape over time and their relation to sex and OA are unknown and may help inform how sex is associated with shape and OA and whether the effect is exerted early or later in life.Questions/purposes (1) Does knee shape segregate stably into different groups of trajectories of change (groups of knees that share similar patterns of changes in bone shape over time)? (2) Do females and males have different trajectories of bone shape changes? (3) Is radiographic OA at baseline associated with trajectories of bone shape changes? METHODS: We used data collected from the NIH-funded Osteoarthritis Initiative (OAI) to evaluate a cohort of people aged 45 to 79 years at baseline who had either symptomatic knee OA or were at high risk of having it. The OAI cohort included 4796 participants (58% females; n = 2804) at baseline who either had symptomatic knee OA (defined as having radiographic tibiofemoral knee OA and answering positively to the question "have you had pain, aching or stiffness around the knee on most days for at least one month during the past 12 months") or were at high risk of symptomatic knee OA (defined as having knee symptoms during the prior 12 months along with any of the following: overweight; knee injury; knee surgery other than replacement; family history of total knee replacement for OA; presence of Heberden's nodes; daily knee bending activity) or were part of a small nonexposed subcohort. From these participants, we limited the eligible group to those with radiographs available and read at baseline, 2 years, and 4 years, and randomly selected participants from each OAI subcohort in a manner to enrich representation in the study of the progression and nonexposed subcohorts, which were smaller in number than the OA incidence subcohort. From these patients, we randomly sampled 473 knees with radiographs available at baseline, 2 years, and 4 years. We outlined the shape of the distal femur and proximal tibia on radiographs at all three timepoints using statistical shape modelling. Five modes (each mode represents a particular type of knee bone shape variation) were derived for the proximal tibia and distal femur's shape, accounting for 78% of the total variance in shape. Group-based trajectory modelling (a statistical approach to identify the clusters of participants following a similar progression of change of bone shape over time, that is, trajectory group) was used to identify distinctive patterns of change in the bone shape for each mode. We examined the association of sex and radiographic OA at baseline with the trajectories of each bone shape mode using a multivariable polytomous regression model while adjusting for age, BMI, and race. RESULTS: Knee bone shape change trajectories segregated stably into different groups. In all modes, three distinct trajectory groups were derived, with the mean posterior probabilities (a measure of an individual's probability of being in a particular group and often used to characterize how well the trajectory model is working to describe the population) ranging from 84% to 99%, indicating excellent model fitting. For most of the modes of both the femur and tibia, the intercepts for the three trajectory groups were different; however, the rates of change were generally similar in each mode. Females and males had different trajectories of bone shape change. For Mode 1 in the femur, females were more likely to be in trajectory Groups 3 (odds ratio 30.2 [95% CI 12.2 to 75.0]; p < 0.001) and 2 than males (OR 4.1 [95% CI 2.3 to 7.1]; p < 0.001); thus, females had increased depth of the intercondylar fossa and broader shaft width relative to epicondylar width compared with males. For Mode 1 in the tibia, females were less likely to be in trajectory Group 2 (OR 0.5 [95% CI 0.3 to 0.9]; p = 0.01) than males (that is, knees of females were less likely to display superior elevation of tibial plateau or decreased shaft width relative to head width). Radiographic OA at baseline was associated with specific shape-change trajectory groups. For Mode 1 in the femur, knees with OA were less likely to be in trajectory Groups 3 (OR 0.4 [95% CI 0.2 to 0.8]; p = 0.008) and 2 (OR 0.6 [95% CI 0.3 to 1.0]; p = 0.03) than knees without OA; thus, knees with OA had decreased depth of the intercondylar fossa and narrower shaft width relative to epicondylar width compared with knees without OA. For Mode 1 in the tibia, knees with OA were not associated with trajectory. CONCLUSIONS: The shapes of the distal femur and proximal tibia did not change much over time. Sex and baseline knee radiographic OA status are associated with the trajectory of change in the bone's shape, suggesting that both may contribute earlier in life to the associations among trajectories observed in older individuals. Future studies might explore sex-related bone shape change earlier in life to help determine when the sex-specific shapes arise and also the degree to which these sex-related shapes are alterable by injury or other events. LEVEL OF EVIDENCE: Level III, prognostic study.

Genomic Contextualism: Shifting the Rhetoric of Genetic Exceptionalism.

As genomic science has evolved, so have policy and practice debates about how to describe and evaluate the ways in which genomic information is treated for individuals, institutions, and society. The term genetic exceptionalism, describing the concept that genetic information is special or unique, and specifically different from other kinds of medical information, has been utilized widely, but often counterproductively in these debates. We offer genomic contextualism as a new term to frame the characteristics of genomic science in the debates. Using stasis theory to draw out the important connection between definitional issues and resulting policies, we argue that the framework of genomic contextualism is better suited to evaluating genomics and its policy-relevant features to arrive at more productive discussion and resolve policy debates.

Tool for osteoarthritis risk prediction (TOARP) over 8 years using baseline clinical data, X-ray, and MRI: Data from the osteoarthritis initiative.

BACKGROUND: Osteoarthritis (OA), a multifactorial disease causing joint degeneration, often leads to severe disability. The rising rates of disability highlight the need for implementing preventative measures at early stages of the disease, which would especially benefit subjects at high risk for OA development. PURPOSE: To develop a risk prediction tool for moderate-severe OA (TOARP) over 8 years based on subject characteristics, knee radiographs, and MRI data at baseline using data from the Osteoarthritis Initiative (OAI). STUDY TYPE: Retrospective. SUBJECTS: 641 subjects with no/mild radiographic OA (Kellgren-Lawrence [KL] 0-2) and no clinically significant symptoms (Western Ontario and McMaster Universities Arthritis Index [WOMAC] 0-1) were selected from the OAI. FIELD STRENGTH/SEQUENCE: MR images were obtained using 3.0T. ASSESSMENT: Compartment-specific cartilage and meniscus morphology and cartilage T2 were assessed. Baseline subject demographics, risk factors, KL score, cartilage WORMS score, presence of meniscus tear, and cartilage T2 were used to predict the development of moderate/severe OA (KL = 3-4 or WOMAC pain ≥5 or total knee replacement [TKR]) over 8 years. STATISTICAL TESTS: Best subsets variable selection followed by cross-validation were used to assess which combinations of variables best predict moderate/severe OA. RESULTS: Model 1 included KL score, previous knee injury in the last 12 months, age, gender, and BMI. Model 2 included all variables in Model 1 plus presence of cartilage defects in the lateral femur and patella, and presence of a meniscal tear. Model 3 included all variables in Models 1 and 2, plus cartilage T2 in the medial tibia and medial femur. Compared to Model 1 (cross-validated AUC = 0.67), Model 3 performed significantly better (AUC = 0.72, P = 0.04), while Model 2 showed a statistical trend (AUC = 0.71, P = 0.08). DATA CONCLUSION: We established a risk calculator for the development of moderate/severe knee OA over 8 years that includes radiographic and MRI data. The inclusion of MRI-based morphological abnormalities and cartilage T2 significantly improved model performance. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1517-1526.

Bone shape mediates the relationship between sex and incident knee osteoarthritis.

BACKGROUND: Knee bone shape differs between men and women and the incidence of knee osteoarthritis (OA) is higher in women than in men. Therefore, the purpose of the present study was to determine whether the observed difference in the incidence of knee radiographic OA (ROA) between men and women is mediated by bone shape. METHODS: We randomly sampled 304 knees from the OAI with incident ROA (i.e., development of Kellgren/Lawrence grade ≥ 2 by month 48) and 304 knees without incident ROA. We characterized distal femur and proximal tibia shape on baseline radiographs using Statistical Shape Modeling. If a specific bone shape was associated with the risk of incident ROA, marginal structural models were generated to assess the mediation effect of that bone shape on the relation of sex and risk of incident knee ROA adjusting for baseline covariates. RESULTS: Case and control participants were similar by age, sex and race, but case knees were from higher body mass index (BMI) participants (29.4 vs. 27.0; p < 0.001). Women had 49% increased odds of incident knee ROA compared with men (adjusted odds ratio (OR) = 1.49, 95% Confidence Interval (C.I.): 1.04, 2.12). There was an inconsistent mediation effect for tibial mode 2 between sex and incident knee ROA, with an indirect effect OR of 0.96 (95% C.I.: 0.91-1.00) and a direct effect OR of 1.56 (95% C.I.: 1.08-2.27), suggesting a protective effect for this mode. Similar findings were also observed for the mediation effect of tibia mode 10 and femur mode 4. These shape modes primarily involved differences in the angular relation of the heads to the shafts of the femur and tibia. CONCLUSIONS: Distal femur and proximal tibia bone shapes partially and inconsistently mediated the relationship between sex and incident knee OA. Women had a higher risk of incident ROA, and specific bone shapes modestly protected them from even higher risk of ROA. The clinical significance of these findings warrant further investigation.

Relationship of Trochlear Morphology and Patellofemoral Joint Alignment to Superolateral Hoffa Fat Pad Edema on MR Images in Individuals with or at Risk for Osteoarthritis of the Knee: The MOST Study.

Purpose To determine the relationship of patellofemoral joint alignment and trochlear morphology to superolateral Hoffa fat pad (SHFP) edema on magnetic resonance (MR) images in older adults with or at risk for osteoarthritis of the knee. Materials and Methods Institutional review board approval and written informed consent were obtained from all subjects. The Multicenter Osteoarthritis Study is a prospective cohort study of older adults with or at risk for osteoarthritis of the knee. Subjects were recruited from Birmingham, Alabama, and Iowa City, Iowa. In this cross-sectional study, patellofemoral joint alignment (bisect offset, patellar tilt angle, and Insall-Salvati ratio), trochlear morphology (sulcus angle, lateral and medial trochlear inclination, and trochlear angle) and SHFP edema were assessed on MR images of the knee. Measures of alignment and morphology were divided into quartiles, and SHFP was determined to be present or absent. Separate logistic regression models were used to determine the relationship of each measure of alignment and morphology to the presence of SHFP edema, with adjustments for age, sex, and body mass index. Results SHFP edema was present in 152 (13.4%) of the 1134 knees that were included. When compared with knees with measurements in the lowest quartile, knees with measurements in the highest quartile for trochlear angle, bisect offset, and Insall-Salvati ratios were 1.6 (95% confidence interval [CI]: 1.0, 2.6), 2.3 (95% CI: 1.3, 4.0), and 8.9 (95% CI: 4.7, 16.9) times more likely to show SHFP edema, respectively. No relationship was found between other measures and SHFP edema. Conclusion A more anterior trochlear facet, a more laterally displaced patella, and knees with patella alta were significantly associated with SHFP edema on MR images in subjects with or at risk for osteoarthritis of the knee. © RSNA, 2017.

Evaluation of Chondrocalcinosis and Associated Knee Joint Degeneration Using MR Imaging: Data from the Osteoarthritis Initiative.

OBJECTIVES: To evaluate the ability of different MRI sequences to detect chondrocalcinosis within knee cartilage and menisci, and to analyze the association with joint degeneration. METHODS: Subjects with radiographic knee chondrocalcinosis (n = 90, age 67.7 ± 7.3 years, 50 women) were selected from the Osteoarthritis Initiative and matched to controls without radiographic chondrocalcinosis (n = 90). Visualization of calcium-containing crystals (CaC) was compared between 3D T1-weighted gradient-echo (T1GE), 3D dual echo steady-state (DESS), 2D intermediate-weighted (IW), and proton density (PD)-weighted fast spin-echo (FSE) sequences obtained with 3T MRI and correlated with a semiquantitative CaC score obtained from radiographs. Structural abnormalities were assessed using Whole-Organ MRI Score (WORMS) and logistic regression models were used to compare cartilage compartments with and without CaC. RESULTS: Correlations between CaC counts of MRI sequences and degree of radiographic calcifications were highest for GE (rT1GE = 0.73, P < 0.001; rDESS = 0.68, P < 0.001) compared to other sequences (P > 0.05). Meniscus WORMS was significantly higher in subjects with chondrocalcinosis compared to controls (P = 0.005). Cartilage defects were significantly more frequent in compartments with CaC than without (patella: P = 0.006; lateral tibia: P < 0.001; lateral femur condyle: P = 0.017). CONCLUSIONS: Gradient-echo sequences were most useful for the detection of chondrocalcinosis and presence of CaC was associated with higher prevalence of cartilage and meniscal damage. KEY POINTS: • Magnetic resonance imaging is useful for assessing burden of calcium-containing crystals (CaC). • Gradient-echo sequences are superior to fast spin echo sequences for CaC imaging. • Presence of CaC is associated with meniscus and cartilage degradation.

Parental Perception of Self-Empowerment in Pediatric Pharmacogenetic Testing: The Reactions of Parents to the Communication of Actual and Hypothetical CYP2D6 Test Results.

Concerns about the ethical and social implications of genetics persist as more applications of genetic and genomic technology have become available. Pediatric testing for genetic influences on response to opioids like codeine is one area of application. We interviewed parents of children enrolled in a mixed-methods study following the communication of actual or hypothetical results for CYP2D6, which impacts opioid response. Forty-one parents of children naive to opioids and 42 parents of children previously exposed to opioids participated in qualitative interviews. Findings did not differ by the child's opioid exposure or by actual versus hypothetical results. Parents' responses centered on the experience of the parent(s) and the potential impact of that information on the parent, rather than the result's impact on the child. Parents also emphasized that the results did not impact their perceptions of the child, reaffirming that the child was still "normal" regardless of test result. When asked about the impact of receiving secondary results, parents' responses emphasized how the results would impact their ability to advocate for the child or impact their state of mind. While the answers reflect parents' role as surrogate decision maker for their child, they also reinforced concerns that health care decisions might be influenced by secondary parental concerns as much as by the best interests of the child. Emphasis on the child's "normality" challenges concerns about the impact of genetic essentialism, but further research is required to see whether the type of testing done or the way results were communicated shaped this response.

Semi-quantitative MRI biomarkers of knee osteoarthritis progression in the FNIH biomarkers consortium cohort - Methodologic aspects and definition of change.

BACKGROUND: To describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study. METHODS: We conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time. RESULTS: Seventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p < 0.001). Seventy-three percent of cases and 53 % of controls had at least one area with worsening in cartilage surface area (p < 0.001). More cases experienced worsening in Hoffa- and effusion synovitis than controls (17 % vs. 6 % (p < 0.001); 41 % vs. 18 % (p < 0.001), respectively). CONCLUSIONS: A wide range of MRI-detected structural pathologies was present in the FNIH cohort. More severe changes, especially for BMLs, cartilage and meniscal damage, were detected primarily among the case group suggesting that early changes in multiple structural domains are associated with radiographic worsening and symptomatic progression.