mp-614 - mp-614 - Medical Policies
Genetic Testing for CHARGE Syndrome
Policy Number: MP-614
Latest Review Date: February 2019
Policy Grade: C
DESCRIPTION OF PROCEDURE OR SERVICE:
CHARGE syndrome is a rare genetic condition associated with multiple congenital anomalies. In many individuals, the diagnosis can be made based on clinical findings. However, the phenotype of the disease is highly variable, and some patients do not fulfill the criteria for a definite diagnosis by clinical findings. Sequence analysis of the CHD7 gene detects variants in most individuals with CHARGE syndrome.
Description of CHARGE Syndrome
CHARGE syndrome is a rare genetic condition caused by variants of the CHD7 gene on chromosome 8q12.1. The letters of CHARGE syndrome correspond to clinical features: C = ocular coloboma; H = heart defect; A = atresia choanae; R = retarded growth and development; G = genital hypoplasia; and E = ear anomalies/deafness. However, a number of other malformations are also common in this condition. In particular, hypoplasia of the semicircular canals has emerged as a frequent and distinctive CHARGE malformation.
Newborns with CHARGE syndrome typically have several major congenital malformations that affect vision, hearing, cardiovascular function, growth, development, neurologic function, and overall well-being. Mortality is relatively high in neonates with bilateral choanal atresia, cyanotic cardiac malformations, central nervous system (CNS) malformations, and/or tracheoesophageal fistula. In one series, the death rate was 20% in the first month of life and about 50% by six months of age. A formal epidemiologic study in Canada concluded that those who survived infancy were likely to have long-term survival. Morbidity is chronic and multisystemic. Cognitive outcome is difficult to assess because both motor skills and language do not necessarily reflect intellect in this group. About 75% have some degree of intellectual disability. Among the 25% with normal intelligence, many are well educated and live independently as adults.
Clinical Diagnosis of CHARGE Syndrome
Investigators have conducted an extended debate about the relative importance of certain clinical signs. Consequently, the diagnostic criteria for CHARGE syndrome have been repeatedly revised.
The complete phenotypic spectrum of CHARGE was only revealed after identification of the causative gene in 2004, and the phenotypic spectrum of the disease is highly variable.
A 2012 review proposes that the diagnosis of CHARGE syndrome be considered definite if an individual has four major characteristics or three major and three minor characteristics, criteria initially proposed by Blake (the Blake criteria), and modified by Verloes. Individuals with one or two major characteristics and several minor characteristics would be considered to have probable or possible CHARGE syndrome.
- Ocular coloboma, which may be manifest in the iris and/or the retina, choroid, and optic disc, and sometimes as microphthalmia. (Prevalence 80% to 90% of affected individuals.)
- Choanal atresia or stenosis, which may be unilateral or bilateral. Complete bilateral choanal atresia is a life-threatening emergency in a newborn, because neonates are obligate nose breathers. Some CHARGE patients have a cleft palate, in which case the cleft fulfills this criterion. (Prevalence 50%-60%)
- Cranial nerve (CN) abnormality, including hyposmia or anosmia (CN I), facial palsy (CN VII), auditory nerve hypoplasia causing sensorineural hearing loss (CN VIII), and/or swallowing problems (Prevalence 70% to 90%) with or without aspiration (CN IX and CN X).
- Characteristic auditory manifestation of the external, middle, or inner ear (Prevalence 80%-100%). The external ear is often dysmorphic. A number of ossicular malformations of the middle ear are common. Sensorineural hearing loss is associated with a Mondini malformation of the cochlea, and vestibular dysfunction is caused by aplasia or hypoplasia of the semicircular canals in 95% of individuals with CHARGE. Temporal bone computed tomography (CT) is necessary to diagnose the cochlear and semicircular canal defects.
- Genital hypoplasia in boys is manifest as micropenis and cryptorchidism, and in girls as hypoplastic labia. Puberty may be delayed because of hypogonadotropic hypogonadism. (Prevalence 50%)
- Developmental delays; especially gross motor and language delays, which may be intrinsic qualities or caused by impaired balance, deafness, blindness, hypotonia, surgery, or other chronic illness. (Prevalence100%)
- Congenital cardiac malformations. (Prevalence 80%)
- Short stature, often with postnatal onset. (Prevalence 75%)
- Cleft lip and/or cleft palate. (Prevalence 15%)
- Tracheoesophageal fistula. (Prevalence 15%)
- Distinctive CHARGE facial appearance, consisting of a prominent forehead and a prominent nasal bridge. (Prevalence 75%)
Other, less frequent manifestations include kidney malformations (25%), immunodeficiency, various limb abnormalities, scoliosis, dental problems, omphalocele, brain malformations, attention-deficit/hyperactivity disorder, and various behavioral problems.
The diagnosis of CHARGE syndrome is primarily clinical, based on the use of the diagnostic criteria above.
External ear anomalies, abnormalities of cranial nerve function, semicircular canal hypoplasia, and gross motor delays seem to be consistent phenotypic manifestations in CHARGE syndrome, but fully one third of CHARGE patients will lack choanal atresia and/or ocular coloboma with the most mildly affected showing only abnormal ears and a balance disturbance. Consequently, CHARGE syndrome can closely resemble several other genetic and teratogenic conditions, such as the 22q11.2 deletion syndrome, Kallmann syndrome, VACTERL association, Kabuki syndrome, renal coloboma syndrome, Cat eye syndrome, Joubert syndrome, branchio-oto-renal syndrome, and retinoic embryopathy. In one patient with velo-cardio-facial syndrome in whom the chromosome 22q11.2 microdeletion was ruled out, a CHD7 variant was documented. Several patients with Kallmann syndrome were found to have CHD7 disease-associated variants.
In recognition of this expanding CHARGE phenotype, Bergman et al have proposed a revision of cardinal and supporting features and suggest that CHD7 testing be offered to individuals on the milder end of the phenotypic spectrum. Their algorithmic approach to diagnosis also incorporates temporal bone CT scans as an important but not invariantly necessary component of the diagnostic workup. Although CHARGE syndrome is most often related to a sporadic disease-associated variant, some investigators have proposed that family history (any first-degree relative with at least one major feature of CHARGE) be incorporated into the clinical diagnosis of CHARGE syndrome as a major diagnostic criterion.
Genetics of CHARGE Syndrome
In 2014, certain variants of CHD7, which encodes chromodomain helicase DNA-binding protein, were found to cause CHARGE syndrome. In mouse models, the CHD7 gene has been found to be associated with neural crest migration. Almost all pathogenic variants have proven to be single nucleotide variants, though on rare occasions there may be a chromosomal translocation with a breakpoint within the CHD7 gene. Microdeletions, as would be detected with chromosome microarray testing, are rare and probably occur in no more than 2% of individuals.
Most instances of CHARGE syndrome are sporadic events in a family and appear to be caused by de novo CHD7 disease-associated variants. On rare occasions CHARGE can be inherited as an autosomal dominant condition. Individuals with CHARGE who reproduce have a 50% chance of transmitting the variant to their offspring. Recurrence in siblings because of germline mosaicism has also been reported. The prevalence of CHARGE syndrome is estimated at 1 in 8500 live births.
Genetic testing for variants of CHD7 is commercially available from several commercial laboratories and is generally performed through Sanger sequence analysis. If no disease-associated variant is identified by Sanger sequencing, deletion/duplication analysis can be performed to identify large deletions.
Treatment of CHARGE Syndrome
Extensive management guidelines have been developed for CHARGE syndrome. These include periodic examinations and treatment by ophthalmology, otolaryngology, audiology, occupational therapy, speech therapy, gastroenterology, endocrinology, cardiology, neurology, developmental pediatrics, and genetics. Routine investigations would include choanal CT, nasal endoscopy, brainstem auditory evoked responses, temporal bone CT, swallowing studies, renal ultrasound, gonadotropin testing, echocardiography, brain magnetic resonance imaging, growth hormone testing, and genetic counseling. Immunological assessment should be considered, particularly if patients have recurrent lung or ear infections. Many of these resources might be provided in due course for a child with multiple congenital anomalies in the absence of an exact etiologic diagnosis. However, a number of specific investigations and therapies might not be considered unless CHARGE syndrome was definitively diagnosed on a clinical basis, or, for mildly affected individuals, as the result of genetic testing.
Effective for dates of service on or after November 14, 2015:
Genetic testing for CHARGE syndrome may be considered medically necessary to confirm a diagnosis in a patient with signs/symptoms of CHARGE syndrome when a definitive diagnosis CANNOT be made with clinical criteria.
Genetic testing for CHARGE syndrome is considered not medically necessary and investigational when a definitive diagnosis CAN be made clinically in individuals with ALL four major characteristics OR three major and three minor characteristics.
- Major characteristics include:
- Ocular coloboma
- Choanal atresia or stenosis
- Cranial nerve abnormality
- Ear anomalies/deafness
- Minor characteristics include:
- Genital hypoplasia;
- Hypogonadotropic hypogonadism;
- Developmental delays;
- Cardiac malformations;
- Short stature;
- Cleft lip and/or cleft palate;
- Tracheoesophageal fistula;
- Distinctive CHARGE facial appearance consisting of a prominent forehead and a prominent nasal bridge;
- Other less frequent manifestations include kidney malformations, immunodeficiency, various limb abnormalities, scoliosis, dental problems, omphalocele, brain malformations, attention deficit hyperactivity disorder (ADHD), and various behavior problems
Genetic testing for CHARGE syndrome is considered not medically necessary and investigational in all other situations.
NOTE: This policy does not address preconception (carrier) testing and prenatal (in utero) testing.
The most recent literature review was updated through December 14, 2018.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Testing for Suspected CHARGE Syndrome
Clinical Context and Test Purpose
In many cases, the individual clinical manifestations of CHARGE syndrome would present on their own and require management without a diagnosis of the larger syndrome. However, given the multisystemic nature of the disease and the well-established recommendations for surveillance for early complications, it is highly likely that outcomes are improved for individuals with CHARGE syndrome if a diagnosis is made.
The purpose of genetic testing for CHD7 in patients who have suspected CHARGE is to inform a decision whether to pursue additional management steps for CHARGE.
The questions addressed in this evidence review are: (1) is there evidence that testing for disease-associated variants in CHD7 has clinical validity; and (2) does patient management change in a way that potentially improves outcomes as a result of testing?
The following PICOTS were used to select literature to inform this review.
The population of interest includes patients with signs and/or symptoms of CHARGE syndrome, but who do not meet the clinical definition of CHARGE syndrome.
Most disease-causing variants in CHD7 associated with CHARGE syndrome are single-nucleotide variants; therefore, Sanger sequencing is an appropriate first step in testing. If that is negative, deletion/duplication analysis of the CHD7 gene could be obtained.
The comparator of interest is standard clinical care without genetic testing, where decisions about medical therapy or evaluations are based on symptoms at the time of presentation.
Trials of genetic testing or treatment strategies in this population were not found. Morbidity and mortality over the course of several years given the disease presentation in early childhood would be reasonable.
CHARGE syndrome is likely managed at least in part by subspecialists. Depending on the acuity of the initial presentation, the patient may be an inpatient or an outpatient. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.
Simplifying Test Terms
There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:
- Technically reliable
- Clinically valid
- Clinically useful
Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.
Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.
Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predicting a response to therapy.
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
The yield of genetic testing in individuals with either diagnosed or suspected CHARGE syndrome can vary depending on factors such as age or family history, and may depend on the clinical criteria used. As reported in the Clinical Utility Gene Card (2015), in over 90% of the patients who fulfill the Blake or Verloes criteria, a disease-associated variant is found.
In those with suspected CHARGE syndrome, a disease-associated variant is found in 30% to 60% of patients. The proportion varies in individual studies, especially those with a small sample size. For example, in 2006, Lalani et al tested conducted genetic testing in 110 individuals with a clinical diagnosis of CHARGE syndrome and found disease-associated variants in CHD7 in 64 (58%) of study participants. A 2007 study by Vuorela et al tested 74 patients with suspected CHARGE syndrome and found disease-associated variants in 30 (41%) of them.
CHARGE syndrome sometimes can be excluded if a patient does not fulfill the clinical criteria and does not carry a disease-associated variant or deletion of CHD7. Some conditions that mimic CHARGE syndrome are 22q11 deletion syndrome, VACTERL association, chromosomal disorders (e.g., deletions 3p12p21.2) disorders caused by teratogens (e.g., maternal diabetes, Accutane), and Kallmann syndrome.
The clinical specificity (proportion of patients who do not have the disease who have a negative test) can be dependent on variable factors such as age or family history. The clinical variability of CHARGE syndrome is considerable. If the diagnosis is based on the Blake criteria, some individuals with CHARGE will be missed. The clinical specificity is greater than 95%, because less than 5% of the patients with a CHD7 disease-associated variant do not completely fulfill these criteria. However, it should be taken into account that the mild end of the phenotypic spectrum is not yet completely known.
The penetrance is high, estimated to be 100%, but there is high clinical variability.
The negative clinical predictive value (probability of not developing the disease if the test is negative), assuming an increased risk based on family history, is 100% if the index case in the family has been tested. If the index case in the family has not been tested, it depends on the a priori chance of the index to find a disease-associated variant, which is 60% to 90%.
There are no known genotype-phenotype correlations for specific CHD7 variants and CHARGE syndrome manifestations, and therefore, the phenotype cannot be predicted from the genotype. For example, a 2006 study by Jongmans et al of 107 patients who were tested for CHD7 variants did not identify any obvious genotype-phenotype correlations.
Section Summary: Clinically Valid
Studies of the yield of testing for CHD7 variants suggest that in individuals with suspected CHARGE syndrome, approximately 30-60% will have an identified CHD7 variant. There is high clinical specificity Genetic testing for CHARGE syndrome is very good for confirming a diagnosis, but a negative test does not rule out the disease.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.
Most cases of CHARGE syndrome can be diagnosed clinically using established major and minor criteria. Scanning of the temporal bones often elicits abnormalities in the semicircular canals, which brings more specificity to the diagnosis. However, not all patients fulfill the clinical criteria for CHARGE syndrome, and based on clinical findings, may be considered to have possible or probable CHARGE syndrome. Mildly affected patients may only have one or a few of the features of CHARGE syndrome. Overlapping features with other syndromes may also make a clinical diagnosis challenging. Genetic testing may be useful in patients who do not have the classical CHARGE characteristics and may be at risk for the long-term complications of CHARGE syndrome.
While extensive management guidelines have been developed for CHARGE syndrome, no randomized controlled trials were identified.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
A chain of evidence can be developed based on the clinical validity. In individuals with suspected but not confirmed CHARGE, in whom genetic testing confirms a diagnosis, a definitive diagnosis will likely direct patient care according to established clinical management guidelines for CHARGE syndrome, including referrals to the proper specialists, treatment of manifestations, prevention of secondary complications, and surveillance.
Section Summary: Clinically Useful
Most cases of CHARGE syndrome can be diagnosed through established clinical criteria. However, patients who do not meet clinical criteria due to variability in clinical presentation are likely to benefit from genetic testing for CHARGE syndrome. A definitive genetic diagnosis of CHARGE would direct patient care to established clinical management guidelines for CHARGE syndrome.
Summary of Evidence
For individuals who have signs and/or symptoms of CHARGE syndrome who receive genetic testing for variants in the CHD7 gene, the evidence includes case series. Relevant outcomes are overall survival, test accuracy, test validity, symptoms, morbid events, functional outcomes, quality of life, and resource utilization. The analytic sensitivity and specificity for detecting disease-associated variants in the CHD7 gene are high. Although the clinical sensitivity of testing CHD7 variant testing cannot be specifically defined, over 90% of patients who fulfill the Blake or Verloes criteria for CHARGE syndrome have a CHD7 variant. A definitive diagnosis may end the need for additional testing in the etiologic workup and direct patient care according to established clinical management guidelines for CHARGE syndrome, including referrals to appropriate specialists, treatment of manifestations, prevention of secondary complications, and surveillance. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Practice Guidelines and Position Statements
In 2011, Bergman et al proposed guidelines for CHD7 analysis and state that while the diagnosis of CHARGE syndrome remains primarily a clinical diagnosis, molecular testing can confirm the diagnosis in mildly affected patients.
U.S. Preventive Services Task Force Recommendations
CHARGE, CHARGE syndrome, CHD7, CHD7 gene mutation
APPROVED BY GOVERNING BODIES:
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Genetic tests for CHARGE syndrome are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA has chosen not to require any regulatory review of this test.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Molecular pathology procedure, Level 8 (e.g., analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform); includes CHD7 (chromodomain helicase DNA binding protein 7) (e.g., CHARGE syndrome), full gene sequence
- Bergman JE, Janssen N, Hoefsloot LH, et al. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet. May 2011; 48(5):334-342.
- Blake K, van Ravenswaaij-Arts CM, Hoefsloot L, et al. Clinical utility gene card for: CHARGE syndrome. Eur J Hum Genet. Sep 2011; 19(9).
- Blake KD, Davenport SL, Hall BD, et al. CHARGE association: an update and review for the primary pediatrician. Clin Pediatr (Phila). Mar 1998; 37(3):159-17
- Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: A review. J Paediatr Child Health. Feb 19 201
- Hughes SS, Welsh HI, Safina NP, et al. Family history and clefting as major criteria for CHARGE syndrome. Am J Med Genet A. Jan 2014; 164A (1):48-53.
- Issekutz KA, Graham JM, Jr., Prasad C, et al. An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study. Am J Med Genet A. Mar 15 2005; 133A (3):309-317.
- Jain S, Kim HG, Lacbawan F, et al. Unique phenotype in a patient with CHARGE syndrome. Int J Pediatr Endocrinol. Oct 13 2011; 2011:11.
- Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. Apr 2006; 43(4):306-314.
- Kim Y, Lee HS, Yu JS, et al. Identification of a novel mutation in the CHD7 gene in a patient with CHARGE syndrome. Korean J Pediatr. Jan 2014; 57(1):46-4
- Lalani SR, Hefner MA, Belmont JW, et al. CHARGE Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)1993 (updated Feb 2012).
- Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet. Feb 2006; 78(2):303-314.
- Sanlaville D, Verloes A. CHARGE syndrome: an update. Eur J Hum Genet. Apr 2007; 15(4):389-399.
- Schulz Y, Wehner P, Opitz L, et al. CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance. Hum Genet. Apr 13 2014.
- Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: report of 47 cases and review. Am J Med Genet. Apr 13 1998; 76(5):402-409.
- van Ravenswaaij-Arts CM, Blake K, Hoefsloot L, et al. Clinical utility gene card for: CHARGE syndrome - update 20 Eur J Hum Genet. Nov 2015; 23(11).
- Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. Mar 15 2005; 133A(3):306-308.
- Vuorela P, Ala-Mello S, Saloranta C, et al. Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions. Genet Med. Oct 2007; 9(10):690-694.
- Wong MT, Lambeck AJ, van der Burg M, et al. Immune dysfunction in children with CHARGE syndrome: a cross-sectional study. PLoS One. 2015; 10(11):e0142350.
Medical Policy Panel, August 2015
Medical Policy Group, September 2015 (3): Newly adopted policy.
Medical Policy Administration Committee, October 2015
Available for comment September 29 through November 13, 2015
Medical Policy Panel, February 2017
Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points & References. Mutation Testing” changed to “Genetic Testing” in investigational policy statement but no change in policy statement intent.
Medical Policy Panel, February 2018
Medical Policy Group, March 2018 (2): 2018 Updates to Key Points and References; no changes to policy statement.
Medical Policy Panel, February 2019
Medical Policy Group, February 2019 (9): 2019 Updates to Description and Key Points; no changes to policy statement.
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.
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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.