Results

The medical records of 1096 IBD affected study participants were reviewed for the analysis. Of these individuals, 68 (6.2%) required a change in diagnosis from that originally reported: 35 (51%) had an original diagnosis of UC, 22 (32%) had an original diagnosis of CD, and 11 (17%) were originally diagnosed as having IDC. Change in diagnosis from UC to CD, or from CD to UC, was made in 13 of these 68 subjects (group 1), 17 individuals had their diagnosis changed from UC or CD to IDC (group 2), 27 with an original diagnosis of UC or CD were subsequently reclassified as unaffected (group 3), four patients with an original diagnosis of IDC were recategorised as UC or CD (group 4), and seven patients with an original diagnosis of IDC were reclassified as unaffected (group 5) (table 1).

After review of the clinical, endoscopic, radiological, surgical, and pathological reports of all affected individuals, reasons for change of diagnosis were assessed and shown to fall into four general categories: discordance between the patients' reported history and objective information obtained in the form of endoscopic, surgical, radiological, or histological results (reason 1); change in disease pattern over time such that reports reviewed closer to the time of study entry were different than those that may have been available to the original diagnosing physician (reason 2); data entry error (that is, no change in diagnosis should have been documented) (reason 3); and insufficient information available to confirm the originally reported diagnosis (reason 4). The distribution of these reasons for each of the five groups of diagnostic change are summarised in table 1.

Using Gensim and Genehunter to model various misclassification rates as described above, loss of power to detect linkage of genome wide significance is demonstrated when patients are incorrectly classified and thus not likely to be linked to a presumed susceptibility locus. For a locus with a relatively strong genetic effect (λ_s=3.5), a 10% error rate in classification led to a loss of power of 12% to detect a significant linkage. For loci contributing more modest genetic risks, such as one with λ_s=1.8 or 1.3, the same 10% error rate led to 28.4% and 40.2% loss of power, respectively, to detect significant linkage (table 2).

Discussion

In the current study, 6.2% of 1096 patients with presumed IBD required a change in diagnosis when their clinical records were reviewed and consistent diagnostic criteria applied. When computer data entry errors were eliminated, the actual diagnostic misclassification rate based on clinical criteria was 58/1096 (5.3%). Importantly, the thorough chart review revealed 30 of these 58 individuals to have no evidence of IBD at all. These results are similar to a previous analysis investigating diagnostic change in a population of IBD patients.2 The results of the current study also identify several reasons underlying the need for a change in diagnosis. The most frequent source of misclassification reflects discordance between the patients' history and more objective criteria reported at surgery or endoscopy, or by review of tissue pathology. In addition, amendments to diagnosis occurred secondary to a change in disease pattern over time.15 ,16 Such alterations complicate attempts to correctly classify IBD patients, particularly for genetic studies. Lack of sufficient information in the clinical records to confirm a diagnosis was another common reason for alteration in diagnosis. Many of these patients, for whom classification changed from UC or CD to no IBD, did not meet histological criteria for a diagnosis of IBD or lacked ongoing symptomatology. In this group of patients it therefore appears that the original report of IBD should not have been made as criteria for IBD based on histological evidence were not met and features of chronic inflammation were frequently absent. The tendency of IBD to relapse is thought to be a critical diagnostic criterion, especially in the absence of confirmatory histological data.17 Other studies have suggested that specific histological criteria must exist before a diagnosis of IBD is made.18

While the majority of diagnostic changes in this report involved patients ultimately deemed not to have IBD, a proportion included those with one type of IBD (that is, CD, UC, or IDC) requiring reclassification to another form of IBD. Insufficient numbers of patients within these categories were available to draw conclusions regarding the reasons for these changes but clearly this type of change can have a significant impact on interpretation of IBD genetic studies as evidence exists suggesting some susceptibility loci are particularly relevant to CD or UC rather than to IBD as a whole.19 ,20

In the context of this study, patients were recruited for the purpose of elucidating susceptibility loci for IBD. Thus we performed this analysis to determine what impact, if any, patient misclassification would have on the ability of multipoint linkage analysis to detect chromosomal loci that may be truly linked to disease susceptibility. The modelling carried out in this report demonstrates that even an error rate as low as 10% can lead to a 40% risk that the threshold for significant linkage would not be reached and a false negative result would be obtained. The negative impact of misclassification errors on the power to detect a true linkage is even more pronounced when the presumed locus is one with a relatively modest effect. As demonstrated in table 2, when a λ_s value of 1.8 was employed, even a 5% classification error rate (less than that found in this report) led to 22% loss of power to detect a true linkage; when a λ_s value of 1.3 was used, similar to the λ_sof the IBD1 susceptibility locus on chromosome 16,3 a 5% or 10% misclassification rate resulted in 20% and 40% loss of power, respectively. Thus loci contributing to IBD susceptibility are likely to be particularly sensitive to even a small degree of misclassification of patients.

With available data now indicating the existence of at least four confirmed IBD susceptibility loci, all with relatively small estimated contributions to the total genetic risk for disease, these results underscore the importance of rigorous review of clinical records of all patients entered into IBD genetic studies and the consistent application of diagnostic criteria to these individuals. The difficulties in replicating IBD susceptibility loci and in interpreting the multitude of candidate gene association studies clearly demonstrate the importance of attempting to maintain homogeneity with respect to diagnosis in patient populations studied. It is acknowledged that the overlap between the clinical, endoscopic, and pathological appearances of CD and UC may sometimes make distinction between the two conditions difficult. However, consistent application of predetermined criteria may be extremely useful in these studies.