Optimising clinical performance using test cut-off limits & algorithms

Cut-off limits 

Until recently it has not been possible to adjust the analytical sensitivity of FOBT tests. This is still not possible for existing gFOBTs, with the exception of the simple adjunct of hydrating the specimen prior to testing with Hemoccult SENSA. With Hemoccult SENSA, hydration increases test sensitivity at the expense of specificity, thereby increasing the false positive rate (Mandel et al. 1993; Ransohoff & Sandler 2002). Hemoccult and Hemoccult SENSA have been compared in two large studies (Mandel et al. 1993). As a result of rehydration, the rate of positive results increased more than fourfold, from 2.4 to 9.8%. Sensitivity increased from 80.8% to 92.2% while both specificity and PPV decreased (specificity: 90.4% rehydrated and 97.7% non-rehydrated. PPV: 2.2 rehydrated and 5.6 non-rehydrated). In the study by Levin, Hess & Johnson (1997) the positivity rates were 5% and 14.6% and PPV 14% and 7% respectively for the non-rehydrated and the rehydrated. Rehydration using Hemoccult SENSA increases clinical sensitivity and decreases specificity and positive predictive value. The high positivity rate of this approach renders it unsuitable for population screening.

With iFOBTs that provide a numeric result, it is possible to adjust the cut-off limit to obtain an acceptable compromise between clinical sensitivity and specificity. This manipulation can provide an adequate detection rate from an acceptable cohort of subjects invited for colonoscopy. Several recent papers have addressed the issue of modifying the faecal haemoglobin cut-off limit of iFOBTs including the following studies (Sieg et al. 1999; Castiglione et al. 2000; Nakama, Zhang & Zhang 2001; Castiglione et al. 2002; Launoy et al. 2005; Vilkin et al. 2005; Rozen et al. 2006; Chen et al. 2007; van Rossum et al. 2009). The data are summarised in Table 4.5. By increasing the positive cut-off limit, the test sensitivity and positivity rate decreases and specificity and positive predictive values for colorectal cancer detection increase. It must be appreciated that these studies used different commercial products with different analytical characteristics, and therefore simple comparisons can be misleading. 

Chen found an analytical cut-off limit range of 100–150 ng/mL faecal haemoglobin in an iFOBT to provide an acceptable balance between sensitivity and specificity (Nakama, Zhang & Zhang 2001; Chen et al. 2007). Increasing the cut-off limit to 300 ng/mL brought an increase in specificity that was small for the corresponding decrease in sensitivity and detection of cancers. A recent study by Rossum of 6157 50–75 year old Dutch participants and using a single OC-Sensor collection and OC-Micro analyser concluded that dropping from the standard 100 ng/mL cut-off to 75 ng/mL brought ‘optimal’ results and may be recommended for population screening in the Netherlands (van Rossum et al. 2009). This study also concluded that where colonoscopy capacity is insufficient, a cut-off up to 200 ng/mL would result in minimal false negatives for cancer although more for advanced adenoma. Policy makers are faced with an arbitrary decision based on the balance between missed cancers/advanced adenomas and the cost of colonoscopy