The aim of the O'CLOC study is to compare the prevalence of different stages and types of cataracts (from no opacities to severe cataracts; nuclear, cortical or posterior subcapsular) in an exposed group of interventional cardiologists with an unexposed reference group of non-interventional cardiologists, while taking into account other risk factors for cataracts, use of radiation protection tools, and exposure level.
Population and selection
There are approximately 1700 interventional cardiologists in France: 1000 coronary interventional cardiologists (CICs) and 700 cardiologists specializing in the treatment of cardiac arrhythmias (arrhythmologists or electrophysiologists). Stratification of recruitment according to this distribution of CICs and electrophysiologists make this study the first to study both types of cardiologists exposed to X-Rays. It should therefore be as representative as possible - at least in terms of proportion - of interventional cardiology in France.
The relative youth of the population of cardiologists has presented difficulties previously in studying cataracts in this group, specifically, the absence of data about lens opacities either in the general population for the same age class as cardiologists who could be considered as unexposed (most data concern essentially "senile cataracts"), or in an appropriate control group. That is, information about the background frequency of lens opacities in a reference population is essential. This study will compare a group of exposed individuals (interventional cardiologists chronically exposed to X-rays) to a group of unexposed but otherwise comparable individuals: cardiologists not occupationally exposed to ionizing radiation (non-interventional cardiologists). The O'CLOC design is presented in Figure . French centres employing CICs and arrhythmologists will be selected according to several criteria: employment of at least two interventional cardiologists; balanced distribution of the centres across France; a balanced distribution of public and private hospitals. All cardiologists in the selected centres will be contacted and invited to participate. Only cardiologists at least 40 years old will be included. This age criterion was chosen to ensure occupational exposure to IR for at least 10 years in the exposed group. Subjects with a history of personal medical radiation exposure (radiotherapy, brain scans) will be excluded from both groups. Moreover, non-interventional cardiologists with a cumulative significant history of work in interventional cardiology above one year will also be excluded. To ensure comparability between the exposed and unexposed groups, subjects will be matched by sex and age.
General overview of the O'CLOC study design.
Trained interviewers, blinded to the participants' lens opacity status, will collect all the rest of the data. Individual information will be collected about general characteristics, potential risk factors for cataracts, and history of exposure to medical radiation, both personally and occupationally. The occupational exposure data will be collected in a specific part of the questionnaire (see Table ) that trained interviewers will use to ask the interventional cardiologists about their lifetime occupational activity. This section specifically mentions most common types of procedures: for the CICs, coronary angiography and coronary angioplasty, and for the electrophysiologists, pacemaker or intracardiac defibrillator implantation, pacemaker or intracardiac defibrillator resynchronization, radiofrequency catheter ablation except for atrial fibrillation, and radiofrequency catheter ablation of atrial fibrillation. These distinctions are justified by substantial differences in doses delivered and received by cardiologists [24
Items collected in the questionnaire
To supplement and verify the information collected in the occupational questionnaire, we will use data from the SISERI System (Systéme d'Information de la Surveillance de l'Exposition aux Rayonnement Ionisants), an information system recording occupational dosimetry of potentially exposed French workers, centralized at the IRSN. SISERI will make it possible for us to confirm the occupationally-exposed or unexposed status of the cardiologists enrolled in the O'CLOC study. In particular, we will be able to confirm the unexposed status of eligible non-interventional cardiologists, by their absence from the database or their presence for less than 12 months. SISERI will also provide us with information on individual dosimetry monitoring (based on dosimetry badges used under the lead apron). Depending on the reliability of the doses recorded there, it may also provide us a crude estimation of doses received by cardiologists.
Numerous grading systems exist to detect and assess lens opacities (e.g., AREDS, Baltimore and Oxford, Merriam Focht, LOCS, etc.), and cataracts can be diagnosed according to these methods. In particular, radiation-induced cataracts have often been studied with the Merriam Focht criteria [31
] and the Lens Opacities Classification System (LOCS), a normalized and internationally validated classification system used for the grading and comparison of cataract severity and type [32
]. All participants in our study will undergo an ophthalmologic examination (see Table ) that includes a slit lamp examination of the lens, to enable the diagnosis and grading of cataracts according to the LOCS III classification [32
]. In practice, these examinations will be performed by volunteer ophthalmologists working in or near the cardiologists' centres. When most convenient for the cardiologist and to encourage participation, examinations could be performed by their own ophthalmologists. Both situations might result in the examiner being unmasked to the subject's exposure status, but the use of the LOCS III standardized classification should limit possible bias and ensure the reliability and repeatability of the lens opacity grading. This classification can detect various levels of lens opacities, ranging from stage 1 to stage 5 (severe). Patients with no opacities (before stage 1) are coded as "no opacity", and only they will be considered to have no cataracts. The presence of only a few lens opacities is the signature of a very early cataract or precataract status, and we consider that any stage in the LOCS III classification corresponds to a cataract, from very early (stage 1) to severe (stage 5). The LOCS classification also allows the localization of lens opacities (cortical, nuclear, posterior subcapsular) to be described and will thus permit us to analyze the potential specificity of radiation-induced cataracts.
Items collected during ophthalmologic examination
Sample size considerations
Previous studies of interventional radiology practitioners have focused exclusively on posterior subcapsular lens opacities. Junk et al.
, who included no unexposed group, found cataracts (advanced stages of lens opacities) in 8% of their sample. Extrapolation of the prevalences observed in the Framingham Eye Study [33
], on the other hand, gave a prevalence of approximately 1.5% in the general unexposed population, Applying these figures indicates that we would need a sample size of 146 individuals in each group to have a statistical power of 80% to show a significant difference (p < 0.05). Applying the prevalence observed in other studies (eg. 37.9% in the interventional cardiologists group vs. 12% in the unexposed group in [28
] or 52% to 9% in [29
]) would require either 40 or 16 individuals in each group. The O'CLOC study is intended to consider a variety of different cataract types and stages, Table presents other studies that have examined different exposed populations for such a variety of cataracts. In particular, with a prevalence of 23% in the exposed group [13
] vs. approximately 10% in an unexposed group [33
], 123 individuals in each group would be necessary. Finally, combining all this information, we estimated that the inclusion in our study of 150 subjects in each group would ensure a statistical power of 80% to test our hypothesis of a significant excess of lens opacities of different cataract types and stages in interventional cardiologists.
The study was approved by the local ethics committees: the CCTIRS (Advisory Committee on Information Processing in Health Research), in opinion number 09.079, and the CNIL (National Data Protection Authority) (authorization number: 909138). The Clinical Trial Registration Information is available at http://www.clinicaltrials.gov
(Unique identifier NCT01061463). Participants enrolled in the study provide their written informed consent.
The non-interventional cardiologists included in the study are considered unexposed. A retrospective evaluation of the IR exposure status of the interventional cardiologists will be necessary. We will assign an exposure category level to each interventional cardiologist based on the information collected in the occupational questionnaire and from the SISERI system, as presented above. It will take into account: specialization in interventional cardiology (CICs or electophysiologists), the questionnaire information (we will consider at a minimum: duration of practice, duration of exposure and the numbers performed of each type of procedure, but other variables, such as the use of protection, handedness (left or right), equipment (film or digital), etc., will also be taken into account when possible, data from the literature (quantifying the cumulative number of examinations per physician and extrapolation from literature data about the mean dose for each type of procedure at various points in time, to estimate the total dose received), and information from the SISERI system (as presented above).
To estimate the cataract risk associated with exposure, the analysis will first compare the prevalence of all types and stages of cataracts (e.g., any type/no opacities; any type/any stage; any type/stage1; any type/stage2 cortical/no opacities; cortical/stage1; etc.) between the exposed and unexposed groups. Second, a sensitivity and specificity analysis will further analyze the outcomes to estimate the relative risk of the different types and stages of cataracts associated with interventional cardiology practices, with adjustments for matching variables (age, sex), but also for potential confounders (e.g., myopia and diabetes). Finally, the retrospective evaluation of potential exposure will be used for a qualitative study of the dose-response relation. This analysis, to the extent possible, will be based on exposure levels, will be adjusted for confounders, and will use the unexposed group as the reference group.
Time plan for the O'CLOC study
Participant recruitment began in October 2009 and is planned to continue through January 2011. As of April 2010, 135 cardiologists (105 interventional and 30 non-interventional) have been recruited. The results should be available by 2011 and we will publish our findings, whether they are positive, negative, significant, or not significant.