Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium.
Kerkhof HJ., Meulenbelt I., Akune T., Arden NK., Aromaa A., Bierma-Zeinstra SM., Carr A., Cooper C., Dai J., Doherty M., Doherty SA., Felson D., Gonzalez A., Gordon A., Harilainen A., Hart DJ., Hauksson VB., Heliovaara M., Hofman A., Ikegawa S., Ingvarsson T., Jiang Q., Jonsson H., Jonsdottir I., Kawaguchi H., Kloppenburg M., Kujala UM., Lane NE., Leino-Arjas P., Lohmander LS., Luyten FP., Malizos KN., Nakajima M., Nevitt MC., Pols HA., Rivadeneira F., Shi D., Slagboom E., Spector TD., Stefansson K., Sudo A., Tamm A., Tamm AE., Tsezou A., Uchida A., Uitterlinden AG., Wilkinson JM., Yoshimura N., Valdes AM., van Meurs JB.
OBJECTIVE: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. METHODS: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. RESULTS: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. CONCLUSION: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.