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Mass Screening for Celiac Disease: The Autoimmunity Screening for Kids Study

Stahl, Marisa G. MD, MSCS1; Geno Rasmussen, Cristy PhD, MPH2; Dong, Fran MS2; Waugh, Kathleen MS2; Norris, Jill M. PhD, MPH3; Baxter, Judith MA2; Yu, Liping MD2; Steck, Andrea K. MD2; Frohnert, Brigitte I. MD, PhD2; Liu, Edwin MD1; Rewers, Marian J. MD, PhD2; the ASK Study Group

Author Information
The American Journal of Gastroenterology: January 2021 - Volume 116 - Issue 1 - p 180-187
doi: 10.14309/ajg.0000000000000751



Celiac disease (CD) is a common gluten-mediated autoimmune enteropathy estimated to affect up to 2%–3% of the adolescent population in Colorado (1,2). Current guidelines recommend screening for CD with tissue transglutaminase autoantibodies (TGA) testing in symptomatic individuals and asymptomatic individuals with high-risk features based on a family history of CD, concurrent autoimmune diseases such as type 1 diabetes, and particular genetic syndromes (3). Although classic gastrointestinal symptoms and signs such as diarrhea, abdominal distension, vomiting, and malabsorption commonly prompt evaluation for CD, the nonclassic and subclinical presentations are often overlooked (4–7). In fact, over half of individuals may be asymptomatic at presentation and, therefore, may not be identified by the current recommendations for serologic screening (8,9). Specifically, in an international prospective cohort study of children at genetic risk for CD—The Environmental Determinants of Diabetes in the Young study—the presence of symptoms was a poor predictor of CD autoimmunity (10).

The difficulty of identifying cases based on the presence of symptoms contributes to diagnostic delay that may be over 10 years on average (11). This diagnostic delay has a negative impact on both the patient's overall health and healthcare utilization (12). Untreated CD may lead to significant morbidity including osteoporosis (13), growth stunting (14), infertility (15), neuropathy (16), and gastrointestinal lymphomas (17,18).

Although CD meets many of the World Health Organization criteria for a chronic disease that should be considered for universal screening, screening for CD in asymptomatic persons remains controversial (19). Although treating individuals with symptomatic CD has clear benefit, the natural history of asymptomatic, screening-detected CD regarding its associated morbidities remains largely unknown. Limited studies have suggested that untreated asymptomatic CD autoimmunity may negatively affect growth and bone health (20,21). However, the risk of morbidity must also be balanced with the cost of screening and the social and economic burden of a gluten-free diet.

Although general pediatric population screening studies have been reported from Europe, to our knowledge, the Autoimmunity Screening for Kids (ASK) is the first large scale pediatric screening study in the United States (22–27). ASK screens children simultaneously for CD and type 1 diabetes. The overall objective of the ASK program is to raise awareness of the importance of type 1 diabetes and CD in the community and to reduce the morbidity of delayed diagnosis associated with these conditions. It will also assess the harms and benefits of a mass screening approach. Here, we report the study design and preliminary screening results for CD in the initial 9,973 children screened between January 2017 and July 2018. The screening results for type 1 diabetes will be reported separately.


Study participants

The protocol was approved by the Colorado Multiple Institutional Review Board and includes children aged 1–17 years who live in Colorado. Between January 2017 and July 2018, families at private pediatric practices, community clinics, urgent cares, and the Children's Hospital Colorado and its satellite locations were approached for participation in the study, and the study was advertised both electronically and at community events. Eligible participants were screened for TGA to detect CD autoimmunity and for islet autoantibodies (IAs) to detect presymptomatic type 1 diabetes. Exclusion criteria included those who already carried a diagnosis of type 1 diabetes (children with type 1 diabetes in Colorado are routinely screened for CD), CD, and those who were not fluent in English or Spanish.

Initial screening

The initial screen consisted of a venipuncture or capillary draw at the selected sites. Parents were also asked to fill out basic demographic information, family history, and gluten-free diet information. Parents and children were asked to complete a symptom questionnaire together. CD symptoms were assessed over the past 3 months including diarrhea (defined as 3 or more stools per day), frequent stomach aches or being gassy or bloated, constipation (defined as less than 2 stools/week), vomiting (not associated with illness), difficulty gaining weight, and poor growth (this was assessed over the past 2 years). This symptom questionnaire was administered before the children or parents were aware of autoantibody status. The results of the blood draw were shared with families within approximately 4 weeks. Children who initially screened negative are offered annual free repeat screening. Parents were also given the option of having the study staff share the research results with the child's primary care physician.

Confirmation testing

Children who initially screened positive for TGA or IA were invited back to the Barbara Davis Center for Diabetes for a confirmation visit (see Figure 1, Supplementary Digital Content 1, A venous blood draw was collected to confirm the positive results. Weight and height were also recorded. Parents and children were asked to fill out a more extended CD symptom questionnaire (see Table 1, Supplementary Digital Content 2, Those who confirmed positive with a TGA radiobinding assay (RBA) result ≥2 times the upper limit of normal were referred to the Children's Hospital Colorado Center for Celiac Disease (CCCD) for clinical evaluation. Children with a low positive RBA result (<2 times the upper limit of normal) were referred back to their primary care physician. Not all TGA-positive children were seen at the CCCD. For those who were not, the research team contacted each family for additional information regarding the outcomes specifically about whether the child has been assessed by a gastroenterologist, whether they have undergone an intestinal biopsy, and whether they have adapted a gluten-free diet.

Tissue transglutaminase autoantibody assays

Two highly sensitive assays were used for screening and confirmation testing in all participants. The RBA detects the TGA immunoglobulin A isotype only and has been previously extensively published (28,29). The primary outcome of the ASK study is persistent celiac autoimmunity defined as positivity on 2 consecutive blood draws for RBA TGA at the cutoff value of 0.05 or greater. Higher antibody levels particularly above 10 times the upper limit of normal have been tied to an increased risk of enteropathy.

The electrochemiluminescence assay (ECL) is unique in its ability to detect autoantibodies of the IgA, IgG, IgD, IgE, and IgM isotypes (30,31) and may be helpful in individuals with selective IgA deficiency, those on a low-gluten containing diet, and those positive for TGA IgM only because of a very recent seroconversion. To fully assess the clinical utility of the ECL TGA assay, ASK continues to follow study participants positive only by this assay. However, for the purpose of this report, “confirmed TGA” was defined as the presence of either ECL TGA or RBA TGA at screening and the presence of RBA TGA at the confirmation visit. The total IgA level was not measured.

Study outcomes

The primary outcome of this study is confirmed RBA TGA. The decision to proceed to endoscopic evaluation occurred after clinical referral and was outside of the study protocol. Secondary outcomes include biopsy-proven CD (Marsh 2 or greater); potential CD (positive serology and biopsy with Marsh score <2); a serologic diagnosis of CD compatible with European Society of Pediatric Gastroenterology, Hepatology, and Nutrition criteria (32); persistent autoimmunity being followed on a gluten-containing diet; repeat negative serologic evaluation on a gluten-containing diet at follow-up; and empiric placement on a gluten-free diet by family or pediatrician without diagnostic confirmation.

Statistical analysis

Demographic characteristics of children participating in the screening are presented according to their TGA status as means (± SD) for continuous variables or percentages (%) for categorical variables; they were compared using the Student t test or χ2 tests or Fisher exact tests, respectively. Independent associations between the presence of TGA and age, sex, race/ethnicity, or having a first degree relative with CD were evaluated by multiple logistic regression. Firth logistic regression was used to reduce the bias of binary logistic regression in the analysis of rare events by using a penalized maximum likelihood estimation. Odds ratios (ORs) and 95% confidence intervals were evaluated. The statistical significance level was defined as P < 0.05. Analyses were performed using SAS statistical software (version 9.4; SAS Institute, Cary, NC).


Initial screen

As of July 11, 2018, 9,973 children were screened for celiac autoantibodies. A family history of CD in a first-degree relative was reported in 3.8% of all screened. Overall, 242 children (2.4%) tested TGA+ at the initial screening (Figure 1). Of these, 183 children (75.6%) were positive by both the RBA and ECL assays, 4 children (1.7%) were positive by RBA only, and 55 children (22.7%) screened positive by ECL only. Demographic characteristics of the study participants by the outcome of their initial screening are shown in Table 1. Among the screening-detected cases, 9.9% (24/242) had a first-degree relative with CD and 11.1% (27/242) had a first-degree relative with type 1 diabetes, compared with, respectively, 3.7% and 4.8% in children who tested negative for TGA. Of the TGA-positive children, 15/242 (6.2%) were positive for both TGA and IAs. As of March 5, 2020, 505 children have been rescreened and 6 initially TGA-negative children have become TGA positive.

Figure 1.
Figure 1.:
Screening and confirmation results for transglutaminase autoantibodies (TGA). celiac disease, CD; Conf, confirmation; ECL, electrochemiluminescence assay; RBA, radiobinding assay; TGA, tissue transglutaminase autoantibodies.
Table 1.
Table 1.:
Characteristics of the study population by TGA status at the initial screening test only

At the initial screening, 60 RBA TGA+ subjects (32.1%) reported one or more symptoms of CD. This was not different from the participants who screened negative as 2,970 subjects or 30.5% reported one or more celiac symptoms (P value 0.65). Symptom prevalence at the initial screen is outlined in Table 2. Vomiting was the only symptom found to be distributed differently among the RBA TGA+ and TGA negative groups with a respective frequency of 6.4% vs 3.6% (P value 0.04). The presence of 2 or more symptoms was more common in the TGA+ group compared with the TGA negative group with a respective frequency of 18.7% vs 13.7%, although not statistically significant (P value 0.05). Other assessed individual symptoms including weight loss, poor growth, constipation, stomach aches, and diarrhea were not different between groups. There was also no association between the age at the time of the initial screening and the presence of symptoms at the initial screen (P value 0.12).

Table 2.
Table 2.:
Prevalence of symptoms at the initial screening according to TGA status

Confirmation testing

Of the 242 initially TGA+ children, 185 (76.4%) returned for a confirmation blood draw (Figure 1). The children who did not return for a confirmation visit did not differ regarding demographic characteristics compared with those who did complete the confirmation visit (see Table 2, Supplementary Digital Content 3, Of those who completed the confirmation visit, thus far, 80.5% (149/185 children) were confirmed RBA TGA+, 10.8% (20/185 children) continued to be only ECL TGA+, and 8.6% (16/185 children) were TGA negative by both assays. Therefore, 149 children met the outcome of persistent autoimmunity, but this does not account for children who have not yet returned for their confirmation visit.

Of the 55 children who were initially TGA+ only by ECL, 42 returned for confirmation testing. Twelve of these participants subsequently confirmed positive by RBA and were included in the primary outcome. Twenty children remained positive on ECL only and 10 children were subsequently negative by both RBA and ECL testing.

Per study protocol, 41 participants who had lower-level confirmed RBA TGA+ (less than 2 times the upper limit of normal) were referred to their primary care health providers. The remaining 108 children with higher-level confirmed RBA TGA+ were referred to the CCCD.

Characteristics associated with presence of confirmed RBA TGA+

Independent associations between the presence of confirmed RBA TGA+ and age, sex, race/ethnicity, or having a first degree relative with CD were assessed in multiple logistic regression models (Figure 2 and Table 3). The prevalence of confirmed RBA TGA+ was clearly higher in non-Hispanic white compared with Hispanic children (2.9% vs 0.8%). The association with ethnicity was significant (OR = 3.34; 2.32–4.79) and independent of age, sex, and family history of CD. The presence of CD in a first-degree relative (OR = 1.83; 1.06–3.16) and female sex (OR = 1.43; 1.03–1.98) were also independently associated with confirmed RBA TGA+. Interestingly, children 6–13 years old were nearly twice as likely to express RBA TGA+ than younger children or older teenagers. These associations held true when limiting cases to those with a RBA TGA over 10 times the upper limit of normal (data not shown).

Figure 2.
Figure 2.:
Association of confirmed RBA tissue transglutaminase autoantibodies (TGA)+ cases with demographic characteristics by logistic regression model. AModel adjusted for age, sex, family history of celiac disease, and self-reported ethnicity and race. ORs compare those who confirm positive by RBA with those who initially screened negative. BReference groups included 2–5 yrs for age, male for sex, no family history of celiac disease, and Hispanic for race/ethnicity. AA, African American; CD, celiac disease; NHW, non-Hispanic White; OR, odds ratio; RBA, radiobinding assay.
Table 3.
Table 3.:
Association of confirmed RBA TGA+ status with age, sex, family history of celiac disease, and race/ethnicity, N = 9,973

Follow-up of confirmed positive children

Of the 108 confirmed RBA TGA+ children referred for the follow-up, 62 were seen by a gastroenterologist. The decision to follow-up with a gastroenterologist was associated with the presence of symptoms at their confirmation screen and RBA TGA value. Of note, 80% of children who followed up with a gastroenterologist had symptoms at their confirmation screen, whereas only 61% of children who did not follow-up with a gastroenterologist had symptoms at their confirmation screen (P value 0.039). The mean RBA TGA value was higher among those seen by gastroenterology; those seen by a gastroenterologist had a mean TGA of 0.56, and those who were not seen by a gastroenterologist had a mean TGA of 0.41 (P value 0.013).

Thirty seven children have biopsy-proven CD (Marsh 2 or greater); 3 children have potential CD (positive serology and biopsy with Marsh score <2); 2 children have a serologic diagnosis of CD compatible with the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition criteria; 18 children have persistent autoimmunity and are being followed on a gluten-containing diet; 2 children had negative serologic testing on a gluten-containing diet (not detected at a clinical visit); and 12 children were empirically placed on a gluten-free diet by their family or pediatrician without diagnostic confirmation (Figure 3). Fourteen children have opted not to follow-up clinically for these results because they remain asymptomatic. These represent the preliminary results of the follow-up of confirmed positive children, and efforts are being made to determine the outcomes of the remaining confirmed positive children who have not yet followed up.

Figure 3.
Figure 3.:
Outcomes of participants referred for further evaluation. ESPGHAN diagnosis requires high positive TGA and positive endomysial autoantibody per the 2020 guidelines. Biopsy-proven celiac disease refers to Marsh 2 or greater. Potential celiac disease refers to positive TGA with Marsh 1 or lower. Empiric GFD refers to children placed on a GFD before diagnostic confirmation of celiac disease. Persistent autoimmunity refers to children with positive TGA and being followed on a gluten-containing diet. TGA negative at follow-up refers to children who had a negative serologic evaluation at their follow-up assessment. Asymptomatic and no follow-up refers to children reported to still have no symptoms and, therefore, have not returned for further assessment. ESPGHAN, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition; F/U, follow up; GI, gastroenterology; GFD, gluten-free diet; TGA, tissue transglutaminase autoantibodies.


The ASK study is performing large scale screening for pediatric CD in Colorado, and this is a report of the initial screening results for the first 9,973 children. Although previous screening studies using epidemiologic cohorts, school children, military personnel, blood donors, and health fair attendees have framed CD as common in the United States (7,33–35), the ASK study is the first mass pediatric screening effort of this size for CD in the United States that will be prospectively following the outcomes of children who screen positive. There is a high prevalence of TGA positivity (2.4%) at the initial screening visit. With an 80% positive confirmation rate using the “gold standard” RBA assay, we estimate that at least 1.9% of all screened Colorado children have undiagnosed persistent TGA positivity. This number is not necessarily representative of the Colorado general population because the ASK screened population was enriched with Hispanic children, representing 51.6% of all screened, compared with 21.7% of the Colorado population. These demographic characteristics do affect CD autoimmunity risk; 2.9% of non-Hispanic white children have confirmed TGA positivity, whereas only 0.8% of Hispanic children were positive. The increased prevalence among non-Hispanic white children corroborates previous reports of ethnic differences in the risk of CD, which may be due to a combination of genetic, environmental, and socioeconomic factors (36,37). For example, Hispanic children more commonly carry the lower risk HLA-DQ8 compared with non-Hispanic whites who more commonly carry higher risk HLA-DQ2 alleles (2,38).

In our study, the presence of symptoms generally did not differ between children who screened positive vs those who screened negative at initial testing. In fact, 2/3 of children RBA TGA positive on their initial screening reported no GI symptoms. Of note, even those with the highest TGA levels by RBA and most likely to have CD (32,39) (greater than 10 times the upper limit of normal) were as likely to report symptoms (16/57, 28.1%) as those who were TGA negative (2,970/9,731, 30.5%, P value 0.69). These findings are consistent with a previously reported Finnish targeted screening study of at-risk children (40). Finally, most TGA-positive children (90%) identified through ASK do not have a first-degree relative with CD. Therefore, screening based only on risk factors such as symptoms or family history will miss most cases.

These are the initial findings of mass screening for pediatric CD in a US population. ASK remains uniquely poised in follow-up studies to address several concerns raised by the US Preventive Services Task Force (USPSTF) statement regarding mass screening for CD in asymptomatic individuals. Further follow-up of children diagnosed with CD through ASK—children who were not recognized as symptomatic by their families or healthcare providers—will allow us to study the potential benefits and harms of mass screening. The potential medical benefits of treating screening-identified CD and earlier diagnosis must be balanced with the potential psychosocial and economic burdens of screening-identified CD. Follow-up at the CCCD assesses symptoms, laboratory abnormalities, growth parameters, quality of life, anxiety, and depression to evaluate for these benefits and burdens.

Diagnosing CD through screening may reduce the healthcare utilization and the cost of unrecognized CD (12,41) particularly regarding prescription medication use, primary healthcare visits, and missed days of school. However, screening also increases costs to the healthcare system particularly in the case of false-positive tests, negative biopsies, and close monitoring of asymptomatic individuals who opt to remain on a gluten containing diet. Regarding mass screening for type 1 diabetes through ASK, it could be cost effective, given a certain baseline prevalence of diabetic ketoacidosis and a preexisting infrastructure for screening (42). Although the outcomes of interest may vary between type 1 diabetes and CD, similar methods may be applied to study the cost effectiveness of screening for CD in the future.

Limitations and strengths

The total IgA level is not measured in ASK participants; therefore, individuals with IgA deficiency may have tested false negative on the RBA TGA assay. IgA deficiency remains rare in the healthy population (around 0.4%) and is only slightly higher in the CD population—around 1.9% (43). On the other hand, most of the children with selective IgA deficiency and CD would be picked up by the ECL TGA assay. ASK is planning a substudy to determine in-depth characterization of the immunoglobulin isotypes in children with persistent TGA detectable only by the ECL assay.

Another reason for potential missed cases involve the 1.3% of participating children already on a gluten-free diet at the time of screening; these factors would lead to an underestimation of the true prevalence of undiagnosed pediatric CD autoimmunity in this screened US population.

The follow-up of TGA+ screening-detected cases is ongoing and the full spectrum of clinical outcomes in this population will not be known for several years. Although nearly 20% of the screening-detected TGA+ cases have not yet completed the confirmation visit, their demographic characteristics were not different from those of children who completed confirmation testing. The study has limited resources to offer full clinical evaluation of screening-detected cases, including intestinal biopsy and treatment. Although most of the children complete the clinical evaluation at the CCCD, some may follow-up with private gastroenterologists because of health insurance restrictions, location, or parental preference. The study team is contacting all subjects not seen at the CCCD in an effort to determine their outcomes and to encourage follow-up if not seen elsewhere. However, as already noted, there are 12 children who elect to self-treat with a gluten-free diet without proper diagnosis of CD and without consultation with a dietitian. The potential for lack of proper follow-ups in TGA-positive children remains a limitation and also has ethical considerations.

The strengths of this report include the size of the study population and robust representation of major racial/ethnic groups. To our knowledge, it is currently the only pediatric mass CD screening effort in a general population in the United States. The initial symptom questionnaire was administered before the subject's knowledge of their screening results, limiting recall bias and making the symptoms reported more representative of what would be noted in the primary care setting. Subsequently, the initial symptoms reported may be an indication of who would be screened in the primary care setting under the current USPSTF recommendations and who may be missed.


ASK aims for the eventual implementation of a mass autoimmune screening program that would be feasible in the primary care setting. In this initial report, we find a high prevalence of undiagnosed CD autoimmunity in a screened US population. Most screening-identified children do not have a family history of CD (∼90% without) or symptoms (∼70% without) at the time of screening. Universal screening seems to be the only way to detect all cases of CD and has the potential to reduce diagnostic delay and associated morbidity. A longer follow-up period is needed to properly assess the costs of screening and the effect on morbidity and quality of life of screening-identified children and families (44–47).


Guarantor of the article: Marisa Gallant Stahl, MD, MSCS.

Specific author contributions: M.G.S., C.R.G.-R., E.L, and M.J.R. were involved in study concept and design, analysis and interpretation of the data, drafted the manuscript, critically revised the manuscript for important intellectual content, and approved the final manuscript submitted and authorship list. F.D. and K.W. were involved in study concept and design, analyzed and interpreted the data, did the statistical analysis, critically revised the manuscript for important intellectual content, and approved the final manuscript submitted and authorship list. J.M.N, J.B., L.Y., A.K.S., and B.I.F. were involved in study concept and design, analyzed and interpreted the data, critically revised the manuscript for important intellectual content, and approved the final manuscript submitted and the authorship list.

Financial support: ASK is funded by grant 3-SRA-2018-564-M-N from JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development, LLC. M.G. S. is supported by the NIH training T32DK067009 grant and the SSCD-Beyond Celiac Early Career grant.

Potential competing interests: E.L. serves as a consultant for Takeda Pharmaceuticals and IM Therapeutics. For all other authors, there are no conflicts of interest to disclose.

Study Highlights


  • ✓ CD is common, and most children remain undiagnosed.
  • ✓ Universal screening remains controversial because of limited evidence on associated morbidity and cost of screening.


  • ✓ This study confirms a high prevalence of undiagnosed CD autoimmunity in a population screened in the United States.
  • ✓ Despite the current USPSTF recommendation for symptom-based autoantibody screening, ASK supports previous findings that symptoms were not predictive of a positive celiac autoantibody screen.
  • ✓ Most children who screened positive for CD in this mass screening program did not have a family history of CD.


The ASK Study Group (see appendix, Supplementary Digital Content 4, The ASK Study is funded by JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development, LLC.


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