Study Shows IgA tTG Testing for Celiac Disease is Less Sensitive than Believed

Celiac.com 05/04/2021 - Immunoglobulin A tissue transglutaminase gives doctors a noninvasive way to spot celiac disease, but new research suggests that its sensitivity may be lower than estimated, making it a poor screening test, at least in asymptomatic patients. 

The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity than it actually does, because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy, while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.

Celiac.com Sponsor (A12):
That matters because the disparity could lead to missed celiac diagnoses, because some of those in the negative group could actually have celiac disease.

"What you're missing from when you're calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That's not even coming into your calculation because they're not getting that reference test," said Marisa Stahl, MD, a physician and researcher at the Children's Hospital Colorado Center of Celiac Disease in Aurora. Stahl was not involved in the meta-analysis, but commented on it in an interview.

To determine whether the studies used by USPSTF may have overestimated sensitivity due to verification bias, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues conducted a meta-analysis, in which they reviewed those same nine studies to see the potential impact of verification bias. They then rated each  study as being high, low, or unclear for possible verification bias. In all, they found five studies to be high risk.

The only way to fully correct the bias is to run both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients, and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. But this is almost never done. 

Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. 

USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.

Dr. Stahl was a bit shocked to see that the sensitivity was so much lower than has been traditionally accepted. The data clearly shows that "...the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease," she said. 

Stahl suggests that the problem may be more common in adults, who have a higher incidence of seronegative Celiac disease, though there is no good data on that point, right now.

Clearly reduced sensitivity of IgA tissue transglutaminase (tTG) testing is a big deal, and we're likely to hear more on this, so stay tuned.

Read the full report in the Journal of Clinical Gastroenterology and the abstract pubmed.ncbi.nlm.nih.gov