Wednesday, 4 October 2017

Number of stool specimens

Several studies have now examined the influence of the number of samples used for testing on clinical sensitivity and specificity. Allison takes any positive result from 3 stool samples measured using FlexSure OBT as an indication for referral and shows higher sensitivity for cancer than studies using single stool samples (Allison et al. 2007). Unsurprisingly other studies show agreement with that conclusion (St John et al. 1993; Allison et al. 1996; Knaani & Samuel 1997; Nakama et al. 1999; Greenberg et al. 2000; Nakama, Zhang & Fattah 2000; Rozen, Wong et al. 2003). Nakama et al. using Monohaem, showed sensitivities of 89% for cancer with 3 stools compared with 56% for a single stool (Nakama et al. 1999).

Using Hem-SP, Morikawa showed low sensitivity for cancer using a single-day sample (Morikawa et al. 2005). Rozen et al. (2006) used 3 stools for the OC-Sensor which contrasts with 2-day samples used in Japan (Nakama, Zhang & Fattah 2000) and 1-day biennial testing performed in Italy (Castiglione et al. 2002). The relative insensitivity in the Italian study to lesions in the proximal bowel (16.3 vs 30.7%) raises further doubts about the use of a single-day sample. In a study using OC-Sensor in an at-risk population, Levi et al. (2007) took numeric measurements from three samples and used the highest concentration of the three as the discriminating factor. Recent studies have taken the average concentration from 2 stool measurements as the discriminating parameter, an approach that reduces the positivity rate. 

The use of different cut-off limits and different numbers of stool samples illustrates how programme algorithms can manipulate clinical sensitivities and specificities for the lesions of interest. Chen describes the use of a cost-effectiveness model as a method of determining the optimal cut-off concentration for an iFOBT (Chen et al. 2007). In the study by Levi et al. (2007) using an iFOBT OCMicro, a scatter plot of 2 consecutive samples showed that of those with cancer or adenomas, 21 of 91 had elevated or markedly elevated faecal blood in one sample but were normal in the other. This is further evidence of intermittent or variable bleeding, sample heterogeneity or poor sample technique that will reduce clinical sensitivity. Imperiale (2007) commenting on the paper by Levi in his editorial in Annals of Internal Medicine (Levi et al. 2007), speculated that concentration-related clinical sensitivity and specificity could be used to determine post-test risk. If risk was related to subject age or sex, this would provide more sophisticated criteria for colonoscopy referral than is currently used. 

Guittet et al. (2009b), using a cut-off concentration of 20 ng/mL, reviewed the relative effectiveness of using one sample, one positive from two samples, two positives from two samples or a mean positive from two samples all measured using the Magstream iFOBT. The study concluded that for any sensitivity the mean of two results provided the highest specificity, and at any positivity it provided the highest sensitivity and specificity. It also concluded that one positive from a single specimen was better than one from two specimens and the cut-off should be adjusted to provide an acceptable positivity rate. 

A recent paper by Grazzini et al. (2009) looks at the clinical outcome of biennial population screening in 20 596 residents of Northern and Central Italy aged 50–69 years. The study uses OC-Sensor and compares outcomes from strategies using different cut-off limits (80, 100 and 120 ng/mL), one or two samples and referral criteria based on either one positive or two positive results. No strategy is singled out as preferable, although some show limited benefit. Generally, those strategies resulting in more colonoscopy referrals increase the detection rate, particularly for adenomas, decrease the positive predictive value and cost more. At the annual Digestive Diseases Week conference in 2010 van Roon et al. (2010) illustrated the relationship between positivity rate, detection rate, cut-off limits, the number of samples measured and the use of different algorithms for combining the results. For positivity rates between 4% and 9% the user can obtain similar clinical outcomes by changing the cutoff with either one or two samples. The dilemma for a population-screening programme is where to draw the line between detection rates, cost and the inconvenience and morbidity associated with colonoscopy. The study showed no significant reduction in uptake for the two-sample strategy, but it did require the samples to be stored in a refrigerator. The choice is likely to be influenced greatly by both financial and logistical considerations.  

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