The PROgnostic Value of unrequested Information in Diagnostic Imaging (PROVIDI) Study: rationale and design

The PROVIDI study is designed as a multi-center retrospective case-cohort study. The cohort consists of subjects with routinely made chest CT scans obtained from eight participating hospitals in the Netherlands (Elkerliek Hospital (Elkerliek), Gelre Hospital (Gelre), St. Antonius Hospital (Antonius), Academic Medical Center Amsterdam (AMC), VU University Medical Center (VUMC), University Medical Center Groningen (UMCG), Academic Hospital Maastricht (AZM), and University Medical Center Utrecht (UMCU)), of which the latter five are tertiary referral centers. A case-cohort design offers significant gains in efficiency over a standard cohort study [16], at the cost of increased complexity in data analysis and the addition of a theoretical layer of assumptions about the uniformity of the cohort. The crucial difference from a normal cohort study is that a random control sample of the cohort is selected at baseline to represent the cohort, making it unnecessary to analyse the whole cohort. Each (cluster of) unrequested finding of interest can then be studied in such an individual sub study that combines the cases that suffered outcome(s) relevant to that finding during follow-up with a new random sample of controls that did not. The control group is to be randomly sampled so that the group is twice as large as the case group for the individual sub study. This permits the use of the PROVIDI cohort in the investigation of the prognostic value of a range of unrelated unrequested findings, as well giving researchers the freedom to pursue unforeseen candidate findings as they emerge. Valid absolute risks, which are indispensable to prognostic research, can be readily calculated.

It was not possible to evaluate the extent of clinical follow-up undergone by patients as a result of unrequested findings with this study design. We did not consider this to be a serious limitation as this is rare in practice [6] and at any rate, it would cause an underestimation of the prognostic effect (as those receiving preventative therapies are probably less likely to experience the outcome of interest).

The PROVIDI study was approved by the Medical Ethics Committee of the University Medical Center Utrecht. The need for written informed consent was waived for all patients due to the retrospective design of this study. A privacy protocol was implemented to ensure that no patient information would be visible whilst reading CT scans and no additional information could be obtained from patient’s medical records and no patient would be contacted as a result of this study.

All patients aged 40 years and older who were referred to one of the participating hospitals with an indication for a chest MDCT between January 2002 and the end of December 2005 were evaluated for inclusion in the PROVIDI study (N = 23.443). Patients with suspected primary lung cancer (including mesothelioma) or distant metastatic disease from other types of cancer (excluding haematological malignancies), 9.077 cases in all, were excluded, on the basis that it is highly unlikely that detection of unrequested imaging findings will alter clinical decision making in patients with such a poor prognosis. This selection was first fully evaluated in a pilot study (Table 1, textbox, pilot study). Consequently, the PROVIDI cohort consists of 14.366 patients, and an equal number of chest CT’s. In cases where patients underwent more than one chest CT examination, only the first CT scan of the series was used for analysis. The chest CT’s were obtained with 2-, 4-, 8-, 16-, 32- or 64-slice scanners of different vendors. All types of chest CT protocols, including contrast and non-contrast scans, were eligible for the PROVIDI study. The CT scans were initially assessed by local hospital radiologists, consistent with routine practice. Subsequently, anonymous copies of all images were stored on disk and transferred to the University Medical Center Utrecht. Patient characteristics and information on type of CT protocol used, including section thickness, tube voltage (kVp), tube load (mAs), and the use of a contrast agent, was abstracted from CT reports by a research physician, who also assessed the CT indication from the CT reports.

The specific candidate image findings will differ for each individual study investigating different specific groupings of disease entities and will be selected for their potential prognostic value, as suggested by the available literature and expert opinions from experienced radiologists as well as other clinical specialists and epidemiologists. CT scans will be reviewed, blinded for general scan parameters, CT indication and the outcome status, at a computer workstation, by trained research physicians and supervised by an experienced chest radiologist. Images are to be viewed at standard lung, soft tissue, and bone settings, which are also readily available to radiologists in clinical practice. Reproducibility of image findings will be evaluated and must be sufficient. Some examples of the types of candidate unrequested scan findings are listed in Fig. 2.

Main endpoints of the PROVIDI study—established after a first initial linkage—are listed in Table 2. Ideal endpoints would be prevalent diseases in with a major clinical impact and can be treated preventively when diagnosed at an early stage. The endpoints were ascertained through linkage with the National Death Registry and the National Registry of Hospital Discharge Diagnoses for the period January 2002-December 2006. Research showed that the quality of these databases was acceptable [17, 18]. Patients were identified through a combination of a patient’s date of birth, sex, and zip code, using a validated probabilistic method [17, 19, 20]. In these databases, cause of death and the occasion of hospitalization are coded according to the International Classification of Disease, 9th [21] and 10th revision [22]. In the initial linkage, performed at a mean followup of 17 months, a total 5.225 out of the 14.366 patient cohort experienced a valid endpoint (Table 2). Note that this initial overview gives only a global indication of the numbers (here death prevailed over admission) and will be updated for each sub study to be performed.

PROVIDI will consist of a series of studies investigating potentially predictive scan findings for specific groupings of disease entities (e.g. cardiovascular diseases). The study populations of these studies will consist of the patients that suffered the relevant disease(s) under study during the follow-up period, as well as a random sample of patients from the PROVIDI cohort (the sub-cohort). In each of these studies, patients with a reported CT indication directly related to the disease under study will be excluded, to ensure that the image findings under study can legitimately be defined as unrequested information, in keeping with the stated goals of PROVIDI. (Table 3, textbox, example study population) Fig. 3 shows the flowchart of the PROVIDI design.

We intend to analyse the scan findings both univariately and multivariately under study using Cox proportional hazard models, the most widely used statistical model for survival outcome in medical research. In multivariate analysis infromation readily available to radiologists in routine care (age, gender, CT indication, scanning parameters and quality) will be incorporated. The hazard ratios and standard errors will be modified based on robust variance estimates. These adaptations are to be carried out using the method according to Prentice, in which all sub cohort members are equally weighted [16]. Cases outside the sub cohort are not to be weighted before failure and at failure receive the same weight as members of the sub cohort. This method has been shown to resemble most closely estimates from a full-cohort analysis [23], without requiring a full analysis.