Multimodal Machine Learning-based Knee Osteoarthritis Progression Prediction from Plain Radiographs and Clinical Data

Knee osteoarthritis (OA) is the most common musculoskeletal disease without a cure, and current treatment options are limited to symptomatic relief. Prediction of OA progression is a very challenging and timely issue, and it could, if resolved, accelerate the disease modifying drug development and ultimately help to prevent millions of total joint replacement surgeries performed annually. Here, we present a multi-modal machine learning-based OA progression prediction model that utilizes raw radiographic data, clinical examination results and previous medical history of the patient. We validated this approach on an independent test set of 3,918 knee images from 2,129 subjects. Our method yielded area under the ROC curve (AUC) of 0.79 (0.78-0.81) and Average Precision (AP) of 0.68 (0.66-0.70). In contrast, a reference approach, based on logistic regression, yielded AUC of 0.75 (0.74-0.77) and AP of 0.62 (0.60-0.64). The proposed method could significantly improve the subject selection process for OA drug-development trials and help the development of personalized therapeutic plans

Risk Factors and Population-Attributable Fractions for Incident Hip Osteoarthritis

Background: Despite the huge burden of hip osteoarthritis (OA) and the lack of effective treatment, research into the primary prevention of hip OA is in its infancy. Purpose: We sought to evaluate risk factors for incident clinical and incident radiographic hip OA among middle-aged and older adults, to evaluate the importance of risk factors from a preventive perspective, and to estimate the percentage of new cases attributable to these risk factors. Methods: We retrospectively reviewed data from the Rotterdam study, an open-population cohort study of individuals aged 55 years or older. Data including baseline age, sex, body mass index, smoking status, education level, diagnosis of diabetes, C-reactive protein (CRP), cam morphology, acetabular dysplasia, radiographic thumb OA, radiographic hip OA, and hip pain were assessed for their association with incident clinical hip OA and incident radiographic hip OA separately, after 11 years of follow-up. The population-attributable fractions (PAFs) of statistically significant modifiable risk factors were calculated, as well. Results: New onset of clinical hip OA was seen in 19.9% (544 of 2729) and incident radiographic hip OA in 9.9% (329 of 3309). Female sex, education level below average (PAF 21.4%), and radiographic hip OA (PAF 3.4%) were statistically significantly associated with incident clinical hip OA. Female sex, age, overweight (PAF 20.0%), cam morphology (PAF 7.9%), acetabular dysplasia (PAF 3.6%), and radiographic thumb OA (PAF 4.7%) were statistically significantly associated with radiographic hip OA. Conclusions: Our retrospective analysis suggests that, from a primary prevention perspective, the most important modifiable risk factors among middle-aged and older individuals may be low educational level for incident clinical hip OA and overweight for incident radiographic hip OA. Further study is warranted.</p

Genetic Variants and Anterior Cruciate Ligament Rupture: A Systematic Review

_Background:_ Studies have shown a familial predisposition for anterior cruciate ligament (ACL) rupture and have been followed by genetic-association studies on polymorphisms in candidate genes in recent years. To date, no systematic review with a best-evidence synthesis has evaluated the influence of genetics on this devastating knee injury. _Objective:_ Our objective was to evaluate the association between genetic variants and ACL rupture. _Methods:_ We performed an extensive search in Embase, MEDLINE, Web of Science, Scopus, PubMed Publisher, Cochrane Register of Clinical Trials, and Google scholar up to 24 August 2015. Studies were eligible if they met the following inclusion criteria: (1) design was a case–control study, retrospective or prospective follow-up study, or a randomized controlled trial (RCT); (2) the study examined the association between a genetic variant and ACL rupture in both an ACL and a control group. We determined the risk of bias for all included studies. _Results:_ We included a total of 16 studies (eight at high risk of bias and eight with an unclear risk) that examined 33 different DNA variants. Conflicting evidence was found for the COL1A1 rs1800012 and COL3A1 rs1800255 variants, whereas limited evidence was found for no association of the COL5A1 rs12722 and rs13946 and COL12A1 rs970547 variants (all encoding collagen). Evidence was insufficient to draw conclusions as to whether any other genetic variant identified in this review had any association with ACL rupture. _Conclusions:_ More research is needed to support a clear association between ACL rupture and genetic variants. Genome-wide studies are recommended for exploring more potential genetic variants. Moreover, large prospective studies are needed to draw robust conclusions

Genetics and biology of vitamin D receptor polymorphisms

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently i

Genetic polymorphisms in the locus control region and promoter of GH1 are related to serum IGF-I levels and height in patients with isolated growth hormone deficiency and healthy controls

Background/Aims: Expression of the human growth hormone (GH) gene (GH1) is regulated by a locus contro

Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene

Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR)possNP=2.41 (95% CI 1.74–3.34, P=1.29 × 10−7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped associa