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Serum Antibodies for the Diagnosis of Inflammatory Bowel Disease

Policy Number: MP-285

Latest Review Date: November 2024

Category: Laboratory

POLICY:

The use of serologic markers is considered investigational for all indications, including but not limited to:

  • antibodies of outer membrane protein C of the bacteria Escherichia Coli (anti-OmpC of e. Coli)
  • anti-chitobioside antibodies (ACCA IgA)
  • anti-flagellin CBir1 (anti-CBir1)
  • anti-laminaribioside antibodies (ALCA IgG)
  • anti-mannobioside antibodies (AMCA IgG)
  • anti-neutrophil cytoplasmic antibodies (ANCA)
  • anti-saccharomyces cerevisiae (ASCA)
  • Pseudomonas fluorescens Chrons disease-associated I2 sequence (P. fluorescens anti-I2)

DESCRIPTION OF PROCEDURE OR SERVICE:

Inflammatory bowel disease (IBD) can be subdivided into ulcerative colitis (UC) and Crohn disease (CD), both of which present with symptoms of diarrhea and abdominal pain. Definitive diagnosis can usually be established by a combination of radiographic, endoscopic, and histologic criteria. In 10%–15% of cases, the distinction between ulcerative colitis and Crohn disease cannot be made with certainty.  

Two serum antibodies, anti-neutrophilic cytoplasmic antibodies (ANCA) and anti- Saccharomyces cerevisiae (ASCA) may have several potential uses. They can be used as diagnostic tests to improve the efficiency and accuracy of diagnosing IBD to decrease the extent of the diagnostic workup or to avoid invasive tests. As a diagnostic test, they might also be useful in differentiating between UC and CD in cases of indeterminate colitis. A second potential use is to classify subtypes of IBD by location of disease (i.e., proximal versus distal bowel involvement) or by disease severity, thereby providing prognostic information. It has also been proposed that these markers may predict response to anti-tumor necrosis factor (TNF) therapy or identify susceptibility to IBD among family members of an affected individual.

The Prometheus© IBD Serology 7 (Prometheus Inc., San Diego, CA) is a quantitative analysis of biomarkers for IBD prediction and differentiation. Prometheus IBD Serology 7 is only offered at Prometheus. This system uses a two-step process to diagnose IBD and to differentiate between UC and CD. The first step is a panel of four markers intended to maximize the sensitivity and negative predictive value of the test. Patients who test positive on the initial screen are further analyzed by a set of proprietary markers and enzyme reagents to distinguish between true positive results and artifacts of fixation. In this way, the Prometheus system is intended to increase the specificity of the test compared to other laboratories. The company also markets a testing strategy for predicting response to anti-TNF therapy and to monitor therapy.

KEY POINTS:

This policy is based evidence review most recently performed on November 5, 2024.

Summary of Evidence

Identified systematic reviews have identified regarding the use of Serum Antibodies for the Diagnosis of Inflammatory Bowel Disease technology. These reviews have found that the technology has relatively low sensitivities and is not completely specific to the inflammatory bowel disease. The clinical utility of this technology has not been demonstrated. No studies have been identified that demonstrate these serum markers could be used in lieu of the standard workup for IBD. No studies have been identified that demonstrate an actual decrease in the number of invasive tests performed because of the use serum markers. Further well-designed scientific studies are needed to evaluate the exact prognostic role of serologic markers which may help in the individual therapeutic management of pediatric and adult IBD. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American College of Gastroenterology (ACG)

Institute for Clinical Systems Improvement (ICSI) Technology Assessment Committee

With regard to serum antibodies for diagnosing inflammatory bowel disease (IBD) the ICSI Technology Assessment Committee finds:

  • The clinical utility of serological testing is not yet established for the diagnosis of inflammatory bowel disease in patients presenting with symptoms suggestive of IBD (Conclusion Grade III).
  • The clinical utility of serological testing is not yet established for differentiating between UC and CD in patients with inflammatory bowel disease (Conclusion Grade II).
  • Although serum testing is a safe procedure, there are risks associated with false negative and false positive test results. Consequences due to false negative and false positive test results have not been evaluated.
  • There are well-established radiologic, histologic, and endoscopic techniques for diagnosing IBD and differentiating CD and UC.
  • There appears to be a high inter-laboratory variability of sensitivities and specificities.

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition / Crohn’s and Colitis Foundation of America

In 2012, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition stated that commercially available serologic assays mail fail to detect CD in at least 30% of children with this disorder and may wrongly suggest a diagnosis of IBD that is not supported by subsequent and definitive (endoscopic study) testing. They further stated that it may be most prudent for primary care providers to avoid ordering these tests and instead pursue referral and more conclusive specialty testing.

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America's consensus conference report on differentiating UC from CD in children and young adults stated that the clinical value of serology in patients with indeterminate colitis (IC) remains a topic of research, and further investigation should ascertain, among other areas, the role of surrogate laboratory markers (e.g., genetics, microbiology, and serology) in distinguishing these entities. A proposed algorithm to aid clinicians in differentiating UC from CD does not include serological testing.

U.S. Preventive Services Task Force

Not applicable.

KEY WORDS:

ANCA, Antibodies for the Diagnosis of Ulcerative Colitis and Crohn’s Disease, ASCA, Crohn’s Disease, (ANCA, ASCA), Prometheus System, Diagnosis of Inflammatory Bowel Disease, Ulcerative Colitis, Prometheus Labs, anti-neutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, DNA testing for Crohn’s disease, inflammatory bowel disease, Prometheus, Prometheus Crohn’s prognostic test for DNA testing, Prometheus NOD2/CARD15, Prometheus IBD sgi diagnostic, IBSchek, Biomarker, Serological antibody, antibodies of outer membrane porin C of the bacteria Eschericia coli, anti-OmpC, Pseudomonas fluorescens-associated sequence I2, anti-I2, flagellin CBir1, anti-cBir1, antichitobioside antibodies, ACCA IgA, antilaminaribioside antibodies, ALCA IgG, antimannobioside antibodies, AMCA IgG

APPROVED BY GOVERNING BODIES:

Serum testing for ANCA and ASCA is not U.S Food and Drug Administration (FDA) approved.

Analysis of anti-neutrophil cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) may be performed in specific reference laboratories, (i.e., Prometheus© Inc.). Prometheus is located in San Diego, CA and licensed in several states including New York and California. It has not been cleared or approved by the U.S. Food and Drug Administration. Prometheus Laboratories Inc. is a CAP accredited CLIA laboratory.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

There is no specific CPT code for detection of ANCA or ASCA. Providers may be using the following nonspecific CPT codes:

82397

Chemiluminescent assay

83516

Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; qualitative or semiquantitative, multiple step method

83520

Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified.

86140

C-reactive protein

88346

Immunofluorescence, per specimen; initial single antibody stain procedure

88350

Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

0164U

Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies, utilizing plasma, algorithm for elevated or not elevated qualitative results (ibs-smart™)

0176U

Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e., ELISA) (IBSSchek®)

PREVIOUS CODING:

CPT codes:

0085U

Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e. ELISA) (Deleted 12/31/2020)

REFERENCES:

  1. Anand V, Russell AS, Tsuyuki R, Fedorak R. Perinuclear antineutrophil cytoplasmic autoantibodies and anti-Saccharomyces cerevisiae antibodies as serological markers are not specific in the identification of Crohn's disease and ulcerative colitis. Can J Gastroenterol. 2008 Jan; 22(1):33-6.
  2. Annese V, Andreoli A, Andriulli A, et al. Familial expression of anti- Saccharomyces cerevisiae Mannan antibodies in Crohn’s disease and ulcerative colitis: A GISC study. Am J Gastroenterol 2001; 96(8): 2407-1
  3. Desplat-Jégo S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, Ballot E, Sarles J, Baudon JJ, Grimaud JC, Veyrac M, Chamouard P, Humbel RL. Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol. 2007 Apr 28; 13(16):2312-8.
  4. Dubinsky MC, Lin YC, Dutridge D, Picornell Y, Landers CJ, Farrior S, Wrobel I, Quiros A, Vasiliauskas EA, Grill B, Israel D, Bahar R, Christie D, Wahbeh G, Silber G, Dallazadeh S, Shah P, Thomas D, Kelts D, Hershberg RM, Elson CO, Targan SR, Taylor KD, Rotter JI, Yang H; Western Regional Pediatric IBD Research Alliance. Serum immune responses predict rapid disease progression among children with Crohn's disease: immune responses predict disease progression. Am J Gastroenterol. 2006 Feb; 101(2):360-7.
  5. Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol. 2001 Mar; 96(3):758-65.
  6. Gupta A, Derbes C, Sellin J. Clinical indications of the use of antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies in the evaluation of inflammatory bowel disease at an academic medical center. Inflamm Bowel Dis. Oct 2005; 11(10):898-902.
  7. Gupta SK, Fitzgerald JF, Croffie JM, et al. Comparison of serological markers of inflammatory bowel disease with clinical diagnosis in children. Inflamm Bowel Dis 2004; 10(3): 240-4.
  8. Institute for Clinical Systems Improvement. Serum antibodies for the diagnosis of inflammatory bowel disease (IBD): pANCA for ulcerative colitis (UC) and ASCA for Crohn's disease (CD) Bloomington MN: Institute for Clinical Systems Improvement (ICSI) 2002
  9. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  10. Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut. Sept 2005; 54(9):1232-6.
  11. Jaskowski TD, Litwin CM, Hill HR. Analysis of serum antibodies in patients suspected of having inflammatory bowel disease. Clin Vaccine Immunol. 2006 Jun; 13(6):655-60.
  12. Joossens S, Reinisch W, Vermeire S, Sendid B, Poulain D, Peeters M, Geboes K, Bossuyt X, Vandewalle P, Oberhuber G, Vogelsang H, Rutgeerts P, Colombel JF. The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology. 2002 May; 122(5):1242-7.
  13. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010 Mar; 105(3):501-23; quiz 524.
  14. Kovács M, Müller KE, Papp M, Lakatos PL, Csöndes M, Veres G. New serological markers in pediatric patients with inflammatory bowel disease. World J Gastroenterol. 2014 May 7; 20(17):4873-82.
  15. Kuna AT. Serological markers of inflammatory bowel disease. Biochem Med (Zagreb). 2013; 23(1):28-42.
  16. Lichtenstein GR, Hanauer SB, Sandborn WJ, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009; 104(2):465-483.
  17. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2018 Apr; 113(4):481-517.
  18. Linskens RK, Mallant-Hent RC, Groothuismink A, Bakker-Jonges LE, van de Merwe JP, Hooijkaas H, et al. Evaluation of serological markers to differentiate between ulcerative colitis and Crohn’s disease: pANCA, ASCA and agglutinating antibodies to anaerobic coccoid rods. Eur J Gastroenterol Hepatol. 2002 Sep 01; 14(9):1013-18.
  19. Lombardi G, Annese V, Piepoli A, et al. Antineutrophil cytoplasmic antibodies in inflammatory bowel disease: Clinical role and review of the literature. Dis Colon Rectum 2000; 43(7): 999-1007.
  20. Mitsuyama K, Niwa M, Takedatsu H, Yamasaki H, Kuwaki K, Yoshioka S, Yamauchi R, Fukunaga S, Torimura T. Antibody markers in the diagnosis of inflammatory bowel disease. World J Gastroenterol. 2016 Jan 21; 22(3):1304-10.
  21. Mokhtarifar A, Ganji A, Sadrneshin M. et al. Diagnostic value of ASCA and atypical p-ANCA in differential diagnosis of inflammatory bowel disease. Middle East J Dig Dis 2014 Apr; 5(2); 93-97.
  22. Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, Landers CJ, Abreu-Martin MT, Rotter JI, Yang H, Targan SR. Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. Gastroenterology. 2004 Feb; 126(2):414-24.
  23. Müller S, Styner M, Seibold-Schmid B, Flogerzi B, Mähler M, Konrad A, Seibold F. Anti-Saccharomyces cerevisiae antibody titers are stable over time in Crohn's patients and are not inducible in murine models of colitis. World J Gastroenterol. 2005 Nov 28; 11(44):6988-94.
  24. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Colitis Foundation of America, Bousvaros A, Antonioli DA, Colletti RB, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: Report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America. J Pediatr Gastroenterol Nutr. 2007; 44(5):653-674.
  25. Oliveira SB, Monteiro IM. Diagnosis and management of inflammatory bowel disease in children. BMJ. 2017 May 31; 357:j2083.
  26. Papp M, Lakatos PL. Serological studies in inflammatory bowel disease: how important are they? Curr Opin Gastroenterol. 2014 Jul; 30(4):359-64.
  27. Papp M, Norman GL, Altorjay I, Lakatos PL. Utility of serological markers in inflammatory bowel diseases: gadget or magic? World J Gastroenterol. 2007 Apr 14; 13(14):2028-36.
  28. Peeters M, Joossens S, Vermeire S, et al. Diagnostic value of anti- Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastroenterol 2001; 96(3): 730-4.
  29. Reese GE, Constantinides VA, Simillis C, et al. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol, October 2006; 101(10): 2410-2422.
  30. Roozendaal C, Kallenberg CG. Are anti-neutrophil cytoplasmic antibodies (ANCA) clinically useful in inflammatory bowel disease (IBD)? Clin Exp Immunol. 1999 May; 116(2):206-13.
  31. Roozendaal C, Pogány K, Hummel EJ, Horst G, Dijkstra G, Nelis GF, Limburg PC, Kleibeuker JH, Kallenberg CG. Titres of anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease are not related to disease activity. QJM. 1999 Nov; 92(11):651-8.
  32. Russell RK, Ip B, Aldhous MC, MacDougall M, Drummond HE, Arnott ID, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Wilson DC, Satsangi J. Anti-Saccharomyces cerevisiae antibodies status is associated with oral involvement and disease severity in Crohn disease. J Pediatr Gastroenterol Nutr. 2009 Feb; 48(2):161-7.
  33. Sabery N, Bass, D. Use of Serologic Markers as a Screening Tool in Inflammatory Bowel Disease Compared With Elevated Erythrocyte Sedimentation Rate and Anemia Pediatrics 2007 119: e193-e199.
  34. Saito H, Fukuda Y, Katsuragi K, et al. Isolation of peptides useful for differential diagnosis of Crohn’s disease and ulcerative colitis. Gut. 2003 Apr; 52(4):535-40.
  35. Sakurai, T., & Saruta, M. (2023). Positioning and Usefulness of Biomarkers in Inflammatory Bowel Disease. Digestion, 104(1), 30–41.
  36. Schoepfer AM, Trummler M, Seeholzer P, et al. Discriminating IBD from IBS: Comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis, January 2008; 14(1): 32-39.
  37. Sura SP, Ahmed A, Cheifetz A, et al. Characteristics of inflammatory bowel disease serology in patients with indeterminate colitis. J Clin Gastroenterol. 2014 Apr; 48(4): 351-355.
  38. Sutton CL, Yang H, Li Z, et al. Familial expression of anti- Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn’s disease. Gut 2000; 46(1): 58-63.
  39. Taddei C, Audrain MA, Reumaux D, et al. Alpha1-antitrypsin phenotypes and anti-neutrophil cytoplasmic auto-antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999; 11(11): 1293-8.
  40. Torres J, Petralia F, Sato T, Wang P, Telesco SE, Choung RS, Strauss R, Li XJ, Laird RM, Gutierrez RL, Porter CK, Plevy S, Princen F, Murray JA, Riddle MS, Colombel JF. Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis. Gastroenterology. 2020 Jul; 159(1):96-104.
  41. Vermeire S, Joossens S, Peeters M, et al. Comparative study of ASCA assays in inflammatory bowel disease. Gastroenterology. 2001; 120(4)827-833.
  42. Wei B, Huang T, Dalwadi H, Sutton CL, Bruckner D, Braun J. Pseudomonas fluorescens encodes the Crohn's disease-associated I2 sequence and T-cell superantigen. Infect Immun. 2002; 70(12):6567-6575.
  43. Zholudev A, Zurakowski D, Young W, et al. Serologic testing with ANCA, ASCA and anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: Diagnostic value and correlation with disease phenotype. Am J Gastroenterol 2004; 99(11): 2235-41.

POLICY HISTORY:

Medical Policy Group, July 2006 (2)

Medical Policy Administration Committee, August 2006

Available for comment August 15-September 28, 2006

Medical Policy Group, July 2008 (1)

Medical Policy Group, July 2010 (1)

Medical Policy Group, June 2012 (1) Update to Description, Key Points and References; no change in policy statement

Medical Policy Group, October 2015 (3): Updates to Description, Key Points, Key Words, Approved Governing Bodies, Coding and References. Policy statement clarified by adding additional serologic markers. No change in policy intent.

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 88346 and new CPT code 88350 to current coding section and moved CPT code 88347 from current coding to previous coding.

Medical Policy Group, June 2019: July 2019 quarterly coding update. Added new CPT code 0085U under Current Coding section.

Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points, References. Removed previous coding section: 83516, 83520, 88346, 88347, and 88350. Added key words: Biomarker, Serological antibody, antibodies of outer membrane porin C of the bacteria Eschericia coli, anti-OmpC, Pseudomonas fluorescens-associated sequence I2, anti-I2, flagellin CBir1, anti-cBir1, antichitobioside antibodies, ACCA IgA, antilaminaribioside antibodies, ALCA IgG, antimannobioside antibodies, AMCA IgG. No changes to policy statement.

Medical Policy Group, November 2019: 2020 Annual Coding Update.  Created Previous Coding Section to include code 0085U.

Medical Policy Group, February 2020 (9): Removed codes 81401 and 81479 from policy.

Medical Policy Group, March 2020: Quarterly coding update. Added new CPT code 0164U to Current Coding.

Medical Policy Group, June 2020: Quarterly coding update.  Added new CPT code 0176U to Current Coding.

Medical Policy Group, October 2020:  2021 Annual Coding Update. Code 0085U was already listed in Previous Coding Section. Added deleted effective date of 12/31/2020.

Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, December 2021 (9): 2021 Updates to Description, Key Points, References. Policy statement updated to correct misspellings and to remove “not medically necessary,” no change to policy intent.

Medical Policy Group, October 2022 (9): 2022 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, October 2023 (5): Reviewed by consensus. Updates to Key Points, Benefit Application, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2024 (5): Reviewed by consensus. Updates to Key Points, Benefit Application, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2024 (5): Reviewed by consensus. Updates to Key Points. No new published peer-reviewed literature available that would alter the coverage statement in this policy.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.