Background and Objectives for the Systematic Review

Context

Celiac disease (CD) is an immune-mediated disorder triggered in genetically-susceptible individuals by ingestion of foods containing gluten, a family of proteins found in particular grains.¹ The prevalence of CD in the United States has been estimated to be approximately one percent,² but appears to be increasing, for reasons that are not clear.³ Risk factors for CD include positive family history, trisomy 21, Turner syndrome, and Williams’s syndrome, as well as several autoimmune diseases.

Clinical signs of CD include aphthous ulcers, low bone density, dermatitis herpetiformis, and other symptoms similar to those of other gastrointestinal disorders among which diarrhea, constipation, nausea, vomiting, and abdominal bloating are common. Its diagnosis therefore is quite complicated because many other factors could be responsible for these symptoms.

CD causes enteropathy of the proximal small intestine resulting in poor absorption of nutrients which may subsequently lead to iron-deficiency anemia, chronic fatigue, failure to thrive, and weight loss.⁴ In young children, malabsorption may cause stunted growth and delayed puberty.⁵ In women, folate deficiency may lead to poor birth outcomes, including developmental disorders. In the long-term, untreated CD may increase the risk for non-Hodgkin lymphoma.⁴

The only known effective treatment for CD is avoidance of gluten-containing foods, which makes correct and timely diagnosis possibly the most important component in the management of the illness. Many experts believe that diagnosis is important for both symptomatic patients and asymptomatic individuals who are at high risk.

The validity and acceptability of the various diagnostic testing regimens and criteria have remained controversial. A number of diagnostic methods have been developed; they include various serology tests, HLA typing, video capsule endoscopy and endoscopic duodenal biopsy (which is considered to be the gold standard). Serology tests include Anti-gliadin antibodies (AGA), IgA & IgG; Anti-tissue Transglutaminase (tTG), IgA & IgG; Endomysial antibodies (EmA), IgA; and the Deamidated Gliadin Peptide (DGP) Antibodies, IgA & IgG. These tests are often used by providers as a panel in order to increase specificity and prevent false positives that are associated with tests that don’t work well under varying circumstances.

Rationale for proposed systematic review

Several systematic reviews and guidelines on diagnosis of CD have been published in the past decade, often with contradictory findings and recommendations. There presently exist at least five published guidelines regarding the diagnosis of CD by recognized research/academic/medical bodies such as the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)⁶ and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)⁷ as well as different systematic reviews by government agencies such as the US Agency for Healthcare Research and Quality (AHRQ)⁸ and the UK National Institute for Clinical Excellence (NICE).⁹

The clinical practice guidelines are complex and recommend different approaches to diagnosis. For example, some guidelines propose a different sequence of tests for diagnosing population groups such as symptomatic vs non-symptomatic patients at increased risk (e.g. ESPGHAN). In addition, although some guidelines (ACG and World Gastroenterology Organization (WGO)) still uphold endoscopic biopsy as the gold standard for confirming diagnosis,^5,10 other guidelines (ESPGHAN) explore the use of other tests to serve as substitutes for biopsy even though it can occasionally lead to diagnostic error e.g. pathologists’ misinterpretation, over-interpretation, and inadequate biopsy sample numbers.

The diagnosis of celiac disease is further complicated by the limitations of the various tests, lack of provider knowledge, and variability in laboratory cut-off levels to indicate “positive” results. On the other hand, as general population screening is not recommended by any professional society, 85% of the population still remains undiagnosed.² There may be a high level of underdiagnoses in some populations (for example, low SES) where CD symptoms may be considered “normal” and not receive medical attention. It is also unknown whether different racial, ethnic or other demographic subgroups may be incorrectly diagnosed or underdiagnosed. In addition, false positives and false negatives may lead to significant consequences, including huge lifestyle changes involved for positive diagnosis as well as potential health harm (nutrient malabsorption, osteoporosis, and lymphoma) from undiagnosed CD.

Therefore, this proposed systematic review will investigate which diagnostic methods (including combinations and sequences) are most accurate for various patient types and assess if methods of diagnosis are associated with improvement in clinical and patient-centered outcomes. This project will incorporate results of previous SRs on test accuracy and update them to reflect results of new studies. It will address test combinations and sequences, and accuracy in specific population groups beyond those addressed in previous reviews.

The Key Questions

AHRQ posted the Key Questions (KQ) on the Effective Health Care Web site for public comment in February, 2014. The EPC refined and finalized the key questions after review of the public comments, taking into consideration prior input from Key Informants. This input is intended to ensure that the key questions are specific and relevant.

In response to the public posting, one commenter representing an association of celiac researchers requested we add a question on who should be tested for CD. The results of this review may be used by patients, providers, policy makers and guideline developers to help inform clinical decision making; however, making direction recommendations is beyond the scope of AHRQ systematic reviews. Other comments requested language clarification regarding which diagnostic methods were being examined for accuracy, and what is meant by direct and indirect adverse effects. To improve clarity, we revised the language slightly and changed the order of the questions. Finally, in response to a comment about how previously negative testing affects test accuracy, we added “patients who previously tested negative for CD” as a population, for subquestion 3f.

The key questions for this systematic review are thus:

Question 1

What is the comparative effectiveness of the different diagnostic methods (various serological tests, HLA typing, video capsule endoscopy, used individually and in combination) compared with endoscopy with biopsy as reference standard, to diagnose Celiac Disease (CD) in terms of:

1. Accuracy (sensitivity, specificity, LR+, LR-, summary ROCs)
2. Intermediate outcomes such as clinical decision making and dietary compliance
3. Clinical outcomes and complications related to CD
4. Patient-centered outcomes such as QOL and symptoms

Question 2

Does accuracy/reliability of endoscopy with duodenal biopsy vary by:

1. pathologist characteristics, i.e. level of experience or specific training?
2. method, i.e. type or number of specimens?
3. length of time ingesting gluten before diagnostic testing?

Question 3

How do accuracy (sensitivity, specificity, LR+, LR-, summary ROCs) and outcomes differ among specific populations? (subgroups of KQ1)

1. Symptomatic patients vs. non-symptomatic individuals at risk
2. Adults (over age 18) versus children & adolescents
3. Children under age 24 months vs. older children
4. Demographics, including race, genetics, geography, SES
5. Patients with IgA deficiency
6. Patients previously testing negative for CD

Question 4

What are the direct adverse effects (i.e. bleeding from biopsy) or harms (related to false positives, false negatives, indeterminate results) associated with testing for CD?

In addition, we identify under PICOTS (Populations, Interventions, Comparators, Outcomes, and Timing) the following areas of consideration for the key questions:

Population(s)

• For KQ 1, 2, and 4:
  • All populations tested for CD
• For KQ 3:
  • Patients with signs and symptoms of Celiac Disease, for example:
    • Diarrhea
    • Constipation
    • Dermatitis
    • Malabsorption (anemia, folate deficiency)
  • Asymptomatic individuals at risk of Celiac Disease
    • Family history
    • Type 1 diabetes
    • Auto-immune disease
    • Turner’s syndrome
    • Trisomy 21
  • Children, under age 24 months vs older children & adolescents
  • Adults (aged 18+)
  • Ethnic and geographic populations
  • Low socioeconomic status (SES)
  • Patients with IgA deficiency
  • Patients previously testing negative for CD

Interventions

• For KQ 1, 3:
  • Endomysial antibodies (EmA) IgA test
  • Anti-tissue Transglutaminase (tTG) IgA test
  • Deamidated Gliadin Peptide (DGP) IgA Antibodies
  • EmA IgG, tTG IgG, and DGP IgG tests for IgA deficient individuals
  • HLA typing
  • Video capsule endoscopy
  • Combinations of the above
• For KQ 4:
  • Endoscopy with biopsy
  • Gluten free diet
• For KQ 3:
  • All of the above

Comparators

• For KQ 1, 3:
  • Endoscopy with duodenal biopsy
• For KQ 2:
  • Repeat biopsy

Outcomes

• For KQ 1a, KQ2 and 3a-f, for accuracy
  • Sensitivity
  • Specificity
  • PPV, NPV, FP, FN
  • Positive and negative likelihood ratios
• For KQ 1b, for clinical decision-making
  • Additional testing for CD
  • Nutritionist advice on gluten-free diet
• Follow up and monitoring by For KQ 1c, for clinical outcomes and complications
  • Nutritional deficits
  • Persistence of villous atrophy on biopsy
  • Lymphomas
• For KQ 1d, for patient-centered outcomes
  • Quality of life
  • Discomfort
  • Bloating
  • Abdominal pain
  • Depression
• For KQ 4, for harms
  • Immediate AEs from biopsy
  • Psychological stress related to false positive results
  • Sequelae of false negatives or indeterminate results

Timing

• For KQ 2
  • Length of time ingesting gluten before biopsy

Setting

• For all KQs
  • Outpatient

Analytic Framework

We provide below an analytic framework to illustrate the population, interventions, outcomes, and adverse effects that will guide the literature search and synthesis for this project.

Methods

In general, this systematic review will follow the procedures of the EPC Methods Guide for Medical Test Reviews.¹¹

Criteria for Inclusion/Exclusion of Studies in the Review

Criteria for inclusion/exclusion of studies in the review are displayed in Table 1 below.

Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

Our literature methods are summarized in Table 2.

Existing reviews that we are considering including (in total or in part) as evidence will be assessed for their PICOTS as well as the methods they used to assess risk of bias. If important domains were excluded from either the risk of bias assessment, we will determine the need to assess the original studies included in those reviews along these domains. We will also assess the quality of existing reviews we include as evidence using the AMSTAR¹³ instrument described below, clearly report the analytic methods used, assess the applicability to the populations of interest, and include the reviews’ complete search strategies in an appendix.

An update search will be conducted after submission of the draft report, while the draft undergoes peer review and public comment.

The DistillerSR software package will be used to manage the search output, screening, and data abstraction. Titles and abstracts identified by the searches will be dually screened and all selections will be accepted without reconciliation for further, full-text review. Two researchers will independently screen each full text article for inclusion in the project, with consensus resolution. The lead investigator or clinical expert will resolve any disagreements. The database can be used to calculate inter-rater reliability statistics of agreement and agreement adjusted for chance (kappa statistic) before resolution of disagreements. Assessment of inter-rater reliability can be used to guard against selection bias in choosing the articles for further review.

Data Abstraction and Data Management

Data collection forms will be designed by the project team in Distiller SR, piloted by the reviewers, further modified, and then the final forms piloted with a random selection of included studies to ensure agreement of interpretation. Studies based on large prospective cohorts will be identified in their Distiller records to ensure data are not duplicated. Study-level data abstracted will include: date study conducted; sample size; subjects’ demographic characteristics, symptoms, and risk factors; study inclusion/exclusion criteria; study design including analytic methods used; diagnostic methods including test manufacturer and reference standard; and any other potential confounders. Each study will be abstracted independently by two experienced researchers who will meet to reconcile any differences. Any irreconcilable differences will be discussed with the lead investigator at weekly meetings. At the project’s end, all abstracted data will be uploaded to the federally-fund Systematic Review Data Repository.

Assessment of Methodological Risk of Bias of Individual Studies

Risk of bias of each included study will be categorized as high, medium, or low, based on the Methods Guide for Diagnostic Tests, Chapter 5 (Santaguida, 2012).¹¹ We will use the QUADAS-2 instrument for studies on test accuracy; domains and items are described in Table 3 below. As mentioned above, we will use the AMSTAR instrument,¹² described in Table 4 below, to assess the quality of existing systematic reviews. Each study will be scored individually by two experienced EPC researchers. Discrepancies will be resolved by an experienced methodologist.

Data Synthesis

Studies that report the sensitivity, specificity, positive and negative predictive value, receiver-operating characteristics, or provide the data to perform such calculations may be potentially included in a synthesis. If three or more studies of the same diagnostic method and comparator report sensitivity and specificity their results may be pooled. Summary Receiver Operating Characteristic (ROC) curves will be estimated by plotting sensitivity versus 1-specificity and “area under the curve” will be calculated. Studies will be weighted by sample size. Sensitivity analyses will be conducted by performing analyses stratified by population characteristics listed in Section II of this protocol when possible. When pooling is not possible, study results will be described narratively, according to comparisons of interest and study design, and presented in summary tables.

Grading the Strength of Evidence (SOE) for Major Comparisons and Outcomes

We will assess the overall strength of evidence for accuracy outcomes using guidance created by experts in systematic reviews for the AHRQ Effective Health Care Program.¹³ This method classifies the grade of evidence as based on five required domains: study limitations, consistency, directness, precision, and publication bias. Three additional domains (plausible confounding, dose-response, and magnitude of effect) will be used if applicable. The grades and their definitions are presented below in Table 5.

Table 6 below, taken from the AHRQ Methods Guide for Medical Test Reviews, briefly describes the methods used to rate each domain. The rating system was originally designed to assess the body of evidence on health care interventions rather than diagnostic tests; thus, assessing these domains presents unique challenges. For example, in assessing the precision of estimates of test performance, it may be difficult to judge whether a particular confidence interval has any practical clinical implications. In addition, there may be no direct evidence to link a specific test with clinical outcomes.

As this project will include existing high quality systematic reviews, we will report any SOE ratings developed by their authors. (Some funding agencies do not require SOE ratings.) We will discuss their methods of evaluating the domains described below. If we feel that their methods are inadequate or do not address an important domain, we will re-evaluate per the table below. Of course, if studies applicable to a Key Question are published after the systematic review, we will evaluate the body of evidence as a whole.

Assessing Applicability

Applicability assessment will be based on the similarity of the populations in terms of characteristics listed in the PICOTs. These include age, gender, ethnicity, geographic location, SES, other risk factors, and symptoms. For example, a test may have high sensitivity and specificity in adults but not in small children, due to biological changes during the life course. These issues will be addressed by KQ3. Setting should not affect applicability, as diagnosis of celiac disease almost always occurs in outpatient settings.

References

1. Rashtak S, Murray JA. Review article: coeliac disease, new approaches to therapy. Aliment Pharmacol Ther. 2012 Apr;35(7):768-81. PMID: 22324389.
2. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012 Oct;107(10):1538-44; quiz 7, 45. PMID: 22850429.
3. Ludvigsson JF, Rubio-Tapia A, van Dyke CT, et al. Increasing Incidence of Celiac Disease in a North American Population. Am J Gastroenterol. 2013 Mar 19PMID: 23511460.
4. See J, Murray JA. Gluten-free diet: the medical and nutrition management of celiac disease. Nutr Clin Pract. 2006 Feb;21(1):1-15. PMID: 16439765.
5. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013 May;108(5):656-76; quiz 77. PMID: 23609613.
6. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005 Jan;40(1):1-19. PMID: 15625418.
7. Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60. PMID: 22197856.
8. Rostom A, Dube C, Cranney A, et al. Celiac disease. Evid Rep Technol Assess (Summ). 2004 Jun(104):1-6. PMID: 15346868.
9. National Institute for Health and Clinical Excellence (NICE). Coeliac disease: Recognition and assessment of coeliac disease. National Institute for Health and Clinical Excellence (NICE). London (UK): 2009 May.
10. Bai J, Fried M, Corazza GR, et al. World Gastroenterology Organisation global guidelines on celiac disease. J. Clin Gastroenterol. 2013;47(2):121-6.
11. Chang SM, Matchar DB, al. e. Methods Guide for Medical Test Reviews. AHRQ. 2012.
12. McNeish AS, Harms HK, Rey J, et al. The diagnosis of coeliac disease. A commentary on the current practices of members of the European Society for Paediatric Gastroenterology and Nutrition (ESPGAN). Arch Dis Child. 1979 Oct;54(10):783-6. PMID: 507902.
13. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10. PMID: 17302989.

Definition of Terms

ACG - American College of Gastroenterology
AGA - Anti-gliadin antibodies
CD - Celiac Disease
DGP - Deamidated Gliadin Peptide (DGP) antibodies
EmA - Endomysial antibodies
ESPGHAN - European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
HLA - Human Leukocyte Antigen
IgA - Immunoglobulin A
IgG - Immunoglobulin G
SES - Socioeconomic status
tTG - Anti-tissue Transglutaminase
WGO - World Gastroenterology Organization

Summary of Protocol Amendments

Not applicable.

Review of Key Questions

AHRQ posted the key questions on the Effective Health Care Program Web site for public comment. The EPC refined and finalized the key questions after review of the public comments, and input from Key Informants and the Technical Expert Panel (TEP). This input is intended to ensure that the key questions are specific and relevant.

Key Informants

Key informants are the end users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the key informant role is to provide input into identifying the Key Questions for research that will inform healthcare decisions. The EPC solicits input from key informants when developing questions for systematic review or when identifying high priority research gaps and needed new research. Key informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Key informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as key informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Technical Experts

Technical experts constitute a multi-disciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes and identify particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicting opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design, and methodological approaches do not necessarily represent the views of individual technical and content experts. Technical experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical experts do not do analysis of any kind nor do they contribute to the writing of the report. They have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Technical experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as technical experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. The EPC considers all peer review comments on the draft report in preparation of the final report. Peer reviewers do not participate in writing or editing of the final report or other products. The final report does not necessarily represent the views of individual reviewers. The EPC will complete a disposition of all peer review comments. The disposition of comments for systematic reviews and technical briefs will be published three months after the publication of the evidence report.

Potential peer reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited peer reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.

EPC Team Disclosures

EPC core team members must disclose any financial conflicts of interest (COI) greater than $1,000 and any other relevant business or professional conflicts of interest. Related financial conflicts of interest that cumulatively total greater than $1,000 will usually disqualify EPC core team investigators. As of February 28, 2014, all project staff members had completed COI forms; none reported any conflict of interest.

Role of the Funder

This project was funded under Contract HHSA-290-2012-00006I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Appendix

CELIAC DISEASE SEARCH METHODOLOGY

KQ1 (DIAGNOSTIC METHODS)

SEARCH #1 (DIAGNOSTIC ACCURACY)

DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/2010-4/3/2014

LANGUAGE: English

SEARCH STRATEGY: "celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND
diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR "Transglutaminases"[Mesh] OR "HLA Antigens"[Mesh] OR iga OR ttg OR dgp OR IGG OR mass screening OR diagnosis[mh] OR biopsy[mh] OR biopsies[mh] OR "deamidated gliadin peptide antibodies" OR Human leukocyte antigen* OR "video capsule endoscopy" OR endoscop* AND
Accura* OR Sensitivity and specificity[mh] OR Sensitivity[tiab] OR Specificity[tiab] OR False positive reactions[mh] OR false positive* OR False negative reactions[mh] OR False negative* OR Predictive value OR predictive value of tests[mh] OR Distinguish* OR Differential* OR Identif* OR Detect* OR valid* OR reliab* OR reproducibility of results

SEARCH #2 (INTERMEDIATE OUTCOMES)

DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/2010-4/3/2014

LANGUAGE: English

SEARCH STRATEGY:"celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND
diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR "Transglutaminases"[Mesh] OR "HLA Antigens"[Mesh] OR iga OR ttg OR dgp OR IGG OR mass screening OR diagnosis[mh] OR biopsy[mh] OR biopsies[mh] OR "deamidated gliadin peptide antibodies" OR Human leukocyte antigen* OR "video capsule endoscopy" OR endoscop* OR misdiagnos* OR undiagnos* AND intermediate outcome* OR decision* OR dietary OR diet OR nutrition* OR eating OR food OR foods OR compliance OR comply OR complying OR patient compliance OR adherence OR (("Decision Making"[Mesh]) OR "Decision Support Systems, Clinical"[Mesh]) OR "Food Habits"[Mesh]

SEARCH #3 (CLINICAL OUTCOMES/COMPLICATIONS)

DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/2010-4/3/2014

LANGUAGE: English

SEARCH STRATEGY: "celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND
diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR "Transglutaminases"[Mesh] OR "HLA Antigens"[Mesh] OR iga OR ttg OR dgp OR IGG OR mass screening OR diagnosis[mh] OR biopsy[mh] OR biopsies[mh] OR "deamidated gliadin peptide antibodies" OR Human leukocyte antigen* OR "video capsule endoscopy" OR endoscop* AND
clinical outcome* OR complication* OR adverse event* OR adverse effect* OR harm* OR enteropathy OR "quality of life" OR villous atrophy OR abdominal OR anemia OR anemic OR (deficien* AND (folic acid OR folate)) OR "Outcome and Process Assessment (Health Care)"[Mesh] OR "complications" [Subheading] OR "adverse effects" [Subheading] OR "Quality of Life"[Mesh] OR "Folic Acid Deficiency"[Mesh]

SEARCH #4 (ADD TERMS “MISDIAGNOS* OR “UNDIAGNOS*”)

DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/2010-4/3/2014

LANGUAGE: English

SEARCH STRATEGY: "celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab]
AND misdiagnos* OR undiagnos*

NOTE – THESE RESULTS WERE INCORPORATED INTO THE PREVIOUS RESULT SETS

SEARCH #1 (DIAGNOSTIC ACCURACY)

DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/2010-4/15/2014

LANGUAGE: English

SEARCH STRATEGY: (“ts”= topical search) ts=("celiac disease" OR "coeliac disease") AND ts=(diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR Transglutaminase* OR iga OR ttg OR dgp OR IGG OR mass screening OR "Human leukocyte antigen*" OR endoscop* OR misdiagnos* OR undiagnos*) AND ts=(Accura* OR Sensitivity OR Specificity OR false positive* OR False negative* OR Predictive value OR Distinguish* OR Differential* OR Identif* OR Detect* OR valid* OR reliab* OR reproducib*)

SEARCH #2 (INTERMEDIATE OUTCOMES):

DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/2010-4/15/2014

LANGUAGE: English

SEARCH STRATEGY: ts=("celiac disease" OR "coeliac disease") AND ts=(diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR Transglutaminase* OR iga OR ttg OR dgp OR IGG OR mass screening OR "Human leukocyte antigen*" OR endoscop* OR misdiagnos* OR undiagnos*) AND ts=(intermediate outcome* OR decision* OR dietary OR diet OR nutrition* OR eating OR food OR foods OR compliance OR comply OR complying OR adherence)

SEARCH #3 (CLINICAL OUTCOMES/COMPLICATIONS)

1. DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/2010-4/15/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: ts=("celiac disease" OR "coeliac disease") AND ts=(diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR Transglutaminase* OR iga OR ttg OR dgp OR IGG OR mass screening OR "Human leukocyte antigen*" OR endoscop* OR misdiagnos* OR undiagnos*) AND ts=("adverse effect*" OR "adverse event*" OR "clinical outcome*" OR complication* OR harm* OR enteropathy OR "quality of life" OR villous atrophy OR abdominal OR anemia OR anemic OR "folic acid" OR folate)
    
2. DATABASE SEARCHED & TIME PERIOD COVERED: Cochrane Databases – 1/1/2010-4/15/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY:"celiac disease" OR "coeliac disease" in Title, Abstract, Keywords
   
   NUMBER OF RESULTS: 65
   
   By database:

• Cochrane Reviews (0)
• Other Reviews (5)
• Trials (54)
• Methods Studies (0)
• Technology Assessments (3)
• Economic Evaluations (3)
• Cochrane Groups (0)

KQ2 (ENDOSCOPY WITH DUODENAL BIOPSY)

1. DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/1990-5/13/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY:"celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND
   endoscopy AND duodenal or duodenum AND biopsy OR biopsies
    
2. DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/1990-5/13/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: TOPIC: ("celiac disease" OR "coeliac disease") AND TOPIC: (endoscop* AND (duodenal or duodenum) AND (biopsy OR biopsies))

KQ3 (POPULATION)

1. DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/1990-5/5/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: "celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR "Transglutaminases"[Mesh] OR "HLA Antigens"[Mesh] OR iga OR ttg OR dgp OR IGG OR mass screening OR diagnosis[mh] OR biopsy[mh] OR biopsies[mh] OR "deamidated gliadin peptide antibodies" OR Human leukocyte antigen* OR "video capsule endoscopy" OR endoscop* OR misdiagnos* OR undiagnos* AND "Ethnic Groups"[Mesh] OR "Minority Groups"[Mesh] OR "Socioeconomic Factors"[Mesh] OR "Continental Population Groups"[Mesh] OR "Demography"[Mesh] OR population* OR symptomatic OR nonsymptomatic OR non-symptomatic OR child OR children OR infant OR infants OR pediatric* OR paediatric* OR demograph* OR race OR racial OR ethnic OR ethnicit* OR minority OR minorities OR genetic* OR geograph* OR region OR regions OR regional OR socioeconom* OR socio-econom* OR economic* OR income OR (iga AND deficien*) OR negative OR country[tiab] OR countries[tiab] OR (prevalence OR prevalen*[tiab] AND "outcome assessment health care"[MeSH Terms] OR Accura* OR Sensitivity and specificity[mh] OR Sensitivity[tiab] OR Specificity[tiab] OR False positive reactions[mh] OR false positive* OR False negative reactions[mh] OR False negative* OR Predictive value OR predictive value of tests[mh] OR Distinguish* OR Differential* OR Identif* OR Detect* OR valid* OR reliab* OR reproducibility of results OR outcome OR outcomes OR treatment outcome OR treatment outcomes NOT case report* OR case reports[pt])
    
2. DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/1990-5/5/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: ts=("celiac disease" OR "coeliac disease") AND ts=( diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR Transglutaminase* OR iga OR ttg OR dgp OR IGG OR mass screening OR "Human leukocyte antigen*" OR endoscop* OR misdiagnos* OR undiagnos*) AND ts=(population* OR symptomatic OR nonsymptomatic OR non-symptomatic OR child OR children OR infant OR infants OR pediatric* OR paediatric* OR demograph* OR race OR racial OR ethnic OR ethnicit* OR minority OR minorities OR genetic* OR geograph* OR region OR regions OR regional OR socioeconom* OR socio-econom* OR economic* OR income OR (iga AND deficien*) OR negative OR country OR countries) AND ts=(Accura* OR Sensitivity OR Specificity OR false positive* OR False negative* OR "predictive value" OR Distinguish* OR Differential* OR Identif* OR Detect* OR valid* OR reliab* OR reproducib* OR outcome* OR prevalen*)

KQ4 (ADVERSE EVENTS)

1. DATABASE SEARCHED & TIME PERIOD COVERED: PubMed – 1/1/2003-5/14/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: "celiac disease "[Mesh] OR "celiac disease"[tiab] OR "coeliac disease"[tiab] AND diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR "Transglutaminases"[Mesh] OR "HLA Antigens"[Mesh] OR iga OR ttg OR dgp OR IGG OR mass screening OR diagnosis[mh] OR biopsy[mh] OR biopsies[mh] OR "deamidated gliadin peptide antibodies" OR Human leukocyte antigen* OR "video capsule endoscopy" OR endoscop* OR misdiagnos* OR undiagnos* AND adverse effect* OR adverse event* OR harm* OR bleeding OR perforat* OR danger* OR safe*[tiab] OR safety[tiab] OR patient safety OR accident*
    
2. DATABASE SEARCHED & TIME PERIOD COVERED: Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH – 1/1/2003-5/14/2014
   
   LANGUAGE: English
   
   SEARCH STRATEGY: ts=("celiac disease" OR "coeliac disease") AND ts=(diagnosis OR diagnoses OR diagnostic OR diagnose OR diagnosing OR endomysial OR transglutaminase* OR serolog* OR antibody OR antibodies OR leucocyte* OR hla OR biopsy OR biopsies OR test OR tests OR testing OR screen OR screening OR screened OR Transglutaminase* OR iga OR ttg OR dgp OR IGG OR mass screening OR "Human leukocyte antigen*" OR endoscop* OR misdiagnos* OR undiagnos*) AND ts=(adverse OR harm* OR danger* OR bleed* OR perforat* OR OR safe* OR accident*)