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Molecular Diagnostics and Genetics |
Departments of1 Laboratory Medicine, 2 Pathology, and 3 Medicine, University of Washington School of Medicine, Seattle, WA.
aAddress correspondence to this author at: University of Washington, Department of Laboratory Medicine, Box 357100, Seattle, WA 98195-7110. Fax 206-598-6189; e-mail mastion{at}u.washington.edu.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: A retrospective utilization review was performed to determine the diagnostic yield of neurogenetic tests ordered during calendar year 2005 at a large academic medical center in the western United States.
Results: Overall, a relevant mutation was identified in 30.2% of the 162 patients tested and in 21.5% of the 121 probands, defined as patients for whom no mutation has been previously identified in a family member. Patients with muscle weakness (n = 65) had a mutation detected in 26.2% of all patients and 23.5% of probands (n = 51), with an estimated testing cost per positive result of $3190. Patients tested for neuropathy (n = 36) had a mutation detected in 27.8% of patients and 22.6% of probands (n = 31), with an estimated cost per positive result of $5955. Patients with chorea (n = 25) had a positive result obtained in 68% of patients and 71.4% of probands (n = 7); the estimated cost per positive test was $440. Other diagnostic categories evaluated include ataxias (n = 18; yield, 11.1%; $7620 per positive), familial stroke or dementia syndromes (n = 8; yield, 12.5%; $6760 per positive), and multisystem mitochondrial disorders (n = 10; yield, 20%; $6485 per positive).
Conclusions: Expert clinicians at a tertiary care center who ordered neurogenetic tests obtained a positive result in 21.5% of patients without previously identified familial mutations. These results can be used for comparison and to help establish utilization guidelines for neurogenetic testing.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neurogenetic disorders are individually rare, with a typical prevalence of <1/10 000. Genetic testing methods are complex and are often subject to intellectual property restrictions. Often there is only 1 CLIA-certified laboratory (or at most a few) offering an individual genetic test, and charges range from several hundred to several thousand dollars per test. In addition, these disorders are complicated and may require evaluation of multiple genetic loci to confirm or exclude a diagnosis. To address this issue, some laboratories offer neurogenetic tests in panels; however, the use of panels may lead to less efficient testing strategies and increased testing charges. In this context, medical centers are seeking ways to encourage clinically efficient and cost-effective test utilization, but limited data are available to guide clinical decision-making. We analyzed the use of neurogenic testing, including the diagnostic yield and cost per positive result, at a university-based tertiary care center.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We conducted a review of laboratory databases to obtain a complete list of patients who had 1 or more neurogenetic tests ordered during calendar year 2005. The databases included the laboratory information system, the laboratory billing system, and a database within the molecular diagnostics laboratory. Neurogenetic testing was defined as molecular testing relating to the diagnosis of familial neuropathies, muscular dystrophies (including muscular dystonias and atrophies), ataxias, choreas, and familial stroke or dementia syndromes. Tests for mitochondrial disorders, including multisystem mitochondrial disorders, were also included for review as long as the individual patient’s symptoms included neurological symptoms, because there is some clinical overlap between mitochondrial disorders and the other neurogenetic disorders considered.
Once cases were identified, one author (K.L.E.) reviewed medical and laboratory records to determine the results and clinical context of testing. Problematic cases, such as those for which classification of results was reported as "indeterminate", were reviewed by a 2nd author (J.F.T.). The following information was recorded:
The majority of the individual genetic tests were ordered infrequently, so tests were grouped into related diagnostic categories to facilitate interpretation of ordering patterns and diagnostic yields (see Table 1
). For clarity, multitest panels were broken down into the individual genetic loci ordered and were predominantly evaluated as such. Because individual tests were at times sent to different laboratories because of clinician and laboratory director preferences and because laboratory charges varied over time, billing records indicated variable test charges for individual test orders. For the sake of simplicity, a typical cost was assigned to each genetic locus tested, and this estimated cost was used to generate aggregate testing costs within diagnostic groups. Estimated costs were based on typical charges in the billing records for tests sent out during 2005, and estimated costs for in-house tests were based on the host institution’s published test charges during 2005. Cost of testing did not include any costs of initial or follow-up clinic visits.
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All tests ordered on an individual patient usually fell into a single diagnostic category, and most individual tests were ordered on patients with only 1 type of presenting symptom. For example, testing for the dysferlin (DYSF)1 gene for a subtype of limb girdle muscular dystrophy (LGMD)2 was performed only on patients presenting with muscle weakness, and all other tests ordered along with DYSF also fell into the "muscle disorder" category. The exceptions were tests for Huntington disease and for mitochondrial disorders. Tests for these 2 entities were ordered on patients with a variety of presenting symptoms and were therefore categorized according to the patient’s primary presenting complaint. For the initial analysis, tests on asymptomatic patients were grouped into the most appropriate symptom category. For example, an asymptomatic patient tested for Huntington disease was included in the chorea group, and an asymptomatic patient tested for myotonic dystrophy was included in the muscular disorder group.
The results were deidentified and summarized using SPSS, with the percentage of patients testing positive (diagnostic yield) used as the main outcome measure. The data were sorted in a variety of ways for evaluation. The initial analysis included all 162 patients for whom a neurogenetic test had been ordered during 2005, to summarize the aggregate utilization and performance of these tests as ordered at the host institution. This analysis included some patients for whom a specific genetic mutation had previously been identified in a family member. A 2nd analysis included only the 121 patients who were probands, defined as patients for whom no mutation has been previously identified in a family member, and excluded all patients for whom a specific mutation had previously been identified in a family member. This included those tested presymptomatically (for whom the pretest probability would be a simple calculation based on the inheritance pattern of the gene and the patient’s family history) and those presenting with concerning symptoms (for whom the pretest probability would be even higher). This 2nd analysis was performed to better reflect the diagnostic acumen of the providers ordering the tests.
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Results |
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The overall results are presented in Table 2
. A relevant mutation was identified in 49 (30.2%) of the 162 patients tested. Retrospective chart review indicated that a total of 282 tests for individual genetic loci on these 162 patients originated from the study institution. Forty-nine (17.4%) of the 282 genetic tests were positive. No patient had more than 1 positive result. The positive rate included 2 patients for whom test results were reported as indeterminate by the performing laboratory. These results were considered molecular and clinical true positives on the basis of an amino acid change affecting a start codon in 1 case and the presence of a frameshift mutation in the other. Seven additional indeterminate results were regarded as clinical negatives, because the testing did not provide a definitive molecular diagnosis. Of the 121 probands, 26 (21.5%) had positive results, and of the 20 patients tested presymptomatically, 7 (35%) had positive results.
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A more detailed analysis of the data is presented in Table 3
. The highest diagnostic yield was in patients presenting with chorea (n = 25), with a positive result obtained in 68.0% of all patients tested and 5 of the 7 probands (71.4%). The only test ordered in this category was for Huntington disease, which has a charge of $300 per test. The estimated total cost per positive test was $440. Patients evaluated for neuropathy (n = 36) had a mutation detected in 27.8% of patients and 22.6% of probands. Eight of the 10 positive results were for PMP22 duplication/deletion tests (charge, $575/test). A total of 96 tests (mean, 2.7 tests per patient) were ordered in this category. Test costs ranged from $525 to $1700 per locus, resulting in an estimated cost per positive result of $5955. Patients presenting with symptoms suggesting a muscle dystrophy or other muscular disorder (n = 65) had a mutation detected in 26.2% of all patients and 23.5% of probands, with an estimated cost per positive result of $3190. A total of 99 individual tests (1.5 tests per patient) were ordered in this diagnostic category, and test costs ranged from $240 to $1850.
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Eighteen patients presented with ataxia. Only 2 positive results (11.1%) were obtained in this diagnostic category, including a result for 1 patient with a known family history of a specific spinocerebellar ataxia (SCA) subtype. The estimated cost per positive result was $7620 (individual test costs ranged from $225 to $2335). Similarly, only 1 (12.5%) of the 8 patients tested for a familial stroke or dementia syndromes had a positive result, and that was for a known familial mutation. The estimated cost per positive result in this patient group was $6760 (individual test costs ranged from $342 to $917). Two (20.0%) of the 10 patients presenting with symptoms suggesting a multisystem mitochondrial disorder (n = 10) had a positive result, 1 of whom had a known familial mutation. The estimated cost per positive result was $3950 (tests ranged from $225 to $1365). When the 6 additional mitochondrial tests that were ordered on patients presenting predominantly with neuropathy, muscle weakness, or ataxia were included, the total diagnostic yield for mitochondrial testing was 12.5%, with an estimated cost per positive result of $6485.
The 2 most commonly ordered specific tests, PMP22 duplication/deletion and Huntington disease, each performed well regarding their diagnostic yield. The test-specific diagnostic yield for PMP22 duplication/deletion testing (n = 27) was 29.6%. The estimated cost per positive test for this individual test was $1940. Two Huntington disease tests were ordered in patients presenting with symptoms primarily suggesting a different diagnostic category (1 ataxia and 1 muscle disorder). When these 2 patients were included, the test-specific diagnostic yield for Huntington testing (n = 27) was 63%, with an estimated cost per positive result of $475.
The diagnostic yield of neurogenetic testing with results stratified by the type of ordering provider, the presence or absence of nongenetic disorders in the differential diagnosis, and the number of genetic loci tested are shown in Table 3
. A total of 19 providers ordered tests on the 162 patients. Eighty-five (52.5%) of the 162 patients had tests ordered by geneticists, some of whom subspecialized in neurogenetics. The diagnostic yield for the 85 patients whose tests were ordered by geneticists was 37.6%, compared with 21.4% for the 56 patients whose tests were ordered by neurologists, 40.0% for the 10 patients whose tests were ordered by physicians specializing in rehabilitation medicine, and 12.5% for 8 patients whose tests were ordered by other physicians (n = 8), including pediatricians and ophthalmologists. A diagnosis was obtained for 44.3% of the 97 patients for whom only genetic disorders were considered in their differential diagnosis, compared with 8.3% of the 60 patients for whom nongenetic disorders were considered. A positive result was obtained in 41.7% of patients for whom only a single genetic locus was tested, compared with 9.1% of patients for whom 2 loci were tested and 10.8% of patients for whom 3 or more loci were tested. Similar patterns for diagnostic yield held for probands.
In some cases in which multiple loci were tested, the tests were ordered in panels. In total, 22 panels were ordered on 21 patients. Ten of these were orders for a panel consisting of SCA 1, 2, 3, 6, and 7. One patient had a broader ataxia panel performed at an outside laboratory, which included testing for all commercially available SCA types, as well as DRPLA. Four patients had mitochondrial panels including at least MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibers), and NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa syndrome). One patient had a panel performed for LGMD, and 6 patients had a variety of panels related to the diagnosis of Charcot-Marie-Tooth (CMT). Of the 22 panels on 21 patients, 2 panels were positive, resulting in a diagnostic yield of 9.5% per patient tested.
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Discussion |
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The percentage of positive results (diagnostic yield) was selected as the main outcome measure because it is easily calculated and should be readily comparable between institutions, although neurogenetic testing is informative whether the results are positive or negative. Diagnostic yield is also better suited to the evaluation of neurogenetic testing than quality-adjusted life years saved (4)(5), which has been used to evaluate cancer syndrome testing and newborn screening, because neurogenetic disorders typically do not affect longevity and/or do not have effective treatments.
The process of establishing a definitive molecular diagnosis for suspected neurogenetic disorders has many benefits. These include genetic counseling and family planning, patient access to appropriate services, and limiting further diagnostic work-up (6). In fact, incorporation of similar molecular genetic testing for connexin 26 mutations [gap junction beta-2 gene (GJB2)] in selected patients early in the diagnostic evaluation of childhood idiopathic sensorineural hearing loss was actually projected to improve cost-effectiveness in a recent evaluation (7). The diagnostic yields obtained in the study of connexin 26 were 18% overall and 38% in selected subgroups, suggesting that genetic testing can be used cost-effectively when diagnostic yields are similar to those obtained in our study.
Our belief is that the relatively high diagnostic yields obtained in this study reflect the overall expertise of providers in the host institution. Although a breakdown by provider type is shown in Table 3
, the intention is to show that nearly all groups of providers had reasonable diagnostic yields and not to draw conclusions regarding the relative performance of various provider types. In addition, as a major referral center with subspecialized providers in the field of neurogenetics, the host institution is likely to see a higher proportion of patients for whom a mutation has already been identified in a family member than would be the case in most practice settings. When these patients present for presymptomatic testing, determination of the pretest probability is a simple calculation based on the inheritance pattern of the gene and the family history of the patient, and therefore the overall diagnostic yield obtained in this study reflects the patient population evaluated as much as the diagnostic acumen of the ordering providers. For comparisons between institutions the more relevant number is the positive result obtained in 21.5% of probands, patients who had not had a mutation identified previously in a family member.
Although our study was primarily a utilization review and was not designed to provide a comprehensive analysis of variables affecting the diagnostic yield of neurogenetic tests, the results suggest some general principles that may be helpful when weighing a decision to test. A large proportion (84%) of the positive results were obtained among probands for whom only genetic disorders were considered in their differential list, with a similar proportion (77%) among patients for whom only a single genetic locus was tested. This finding suggests that positive results may be most likely when the clinical presentation suggests a very specific genetic diagnosis. It is also likely that experienced clinicians use a testing strategy that begins with the most prevalent disease-causing mutation. A specific example would be testing first for PMP22 duplications and deletions in a patient with neuropathy and an appropriate clinical presentation, before proceeding with testing for less prevalent mutations that can also cause hereditary neuropathy.
Likewise, although panels were infrequently ordered among our providers, in some cases such orders were associated with inefficient testing strategies, particularly among less experienced clinicians. When used, panels should be constructed to provide those tests with the highest diagnostic yields; otherwise a reflexive testing strategy should be provided that limits the ordering of tests for very rare molecular subtypes. For example, the clinical presentations of the various SCA subtypes are essentially indistinguishable, so molecular tests for these disorders are typically offered by laboratories and ordered by clinicians in batteries. The practice in many laboratories is to perform testing for the most common subtypes in an initial battery (SCA 1, 2, 3, 6, and 7), followed by testing for less common mutations in a 2nd round of testing. We found this to be the most common practice, with specific subtypes tested only in the setting of a previously identified familial mutation.
In contrast, the bundling on test requisition forms of genetic tests for other entities, such as LGMD and CMT, likely encourages the ordering of these tests in panels by ordering providers. We observed a few instances in which panel ordering led to frankly inappropriate testing, such as testing for genes with an X-linked inheritance pattern when the patient’s family history excluded this possibility. The host institution has a program of active review of unusual sendout requests, including most requests for genetic testing in panels. This protocol likely led to the relatively few orders for panels of this type (only 1 for LGMD and 6 for CMT) in this review, but it may also represent a larger area of inefficiency in facilities in which there is less oversight of test ordering.
The diagnostic yield and cost per positive result did vary widely between the different diagnostic groups, partly reflecting differences in the biology of the genetic entities reviewed. For example, Huntington disease has a highly characteristic clinical presentation and is autosomal dominant and highly penetrant. In addition, testing typically requires evaluation of only a single genetic locus for trinucleotide expansion of the HD gene (although it should be noted that additional testing for other loci may be indicated in some patients). These characteristics resulted in a high diagnostic yield and, when combined with the relatively low cost of Huntington genetic testing, a relatively low cost of less than $500 per positive result. In contrast, each positive result obtained in patients with neuropathy cost more than $5000. Tests in this category do include some more esoteric and expensive entities; however, the high cost per positive result also reflects the need to test multiple genetic loci in many patients, because hereditary peripheral neuropathies can be associated with multiple specific genetic mutations with multiple inheritance patterns. Ataxia also had a much higher cost of $7620 per positive result, associated with a diagnostic yield that was low relative to other diagnostic groups, even among these expert clinicians.
To our knowledge, this study is the first to address the cost per positive result of neurogenetic testing. In this study, cost estimates were limited to laboratory charges alone and did not include costs associated with clinic visits and other diagnostic testing, such as imaging or biopsy. Individual test charges ranged from $225 to up to $2335 per individual genetic locus tested. Most test charges ranged from $300 to $700 per locus, with those requiring gene sequencing tending to be at the more expensive end of the range. A few disorders, including CMT 4F, myotonia congenita, and spastic paraplegia type 4, were associated with costs of 
$2000. For each of these very rare disorders, diagnostic tests require gene sequencing, and each test is offered by only a single clinical laboratory in the United States. Of the 55 distinct diagnostic entities included in this review, tests for 12 were available in-house at the host institution. The majority of the remainder were available from 2 or more clinical laboratories. For 16 of the entities, however, testing was available only from a single laboratory in the United States. Many of these exclusive tests fell within the neuropathy category, but there were other tests within this category that were offered by multiple laboratories. Our study sample was insufficient to allow a broad analysis of the effect on the cost of testing of test methodology or the number of laboratories offering the test.
Much discussion has centered around the effect of exclusive licensing of genetic testing for familial cancer syndromes such as BRCA1 and BRCA2 and the impact of the associated high testing charges on healthcare systems (8)(9). Little attention has been focused on the same issue as it relates to neurogenetic testing, however. The patenting and exclusive licensing of genetic tests restricts the availability of testing and reduces competition, and it can also promote undesirable over-bundling of related tests. Some exclusive licenses applicable to neurogenetic tests are incompletely enforced. Universal enforcement of exclusive testing licenses or limitation of the majority of tests to a sole provider would substantially increase typical test charges, comparable to those seen with BRCA1 testing. For example, the cost per positive result for ataxia testing would increase nearly 7-fold, to >$50 000, if all tests had been obtained from the laboratory that claims exclusive patent rights for many of these tests. This increase reflects both higher per-test cost and test packaging that encourages the ordering of larger panels of tests. Thus, policymakers should be aware that many of the costs per positive result found in this study may be greatly increased in the future because of intellectual property restrictions.
The results of this study should be useful to other institutions to help establish utilization guidelines for neurogenetic testing and should also contribute to a broader dialogue about the appropriate and cost-effective use of this important type of molecular genetic testing.
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Acknowledgments |
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Financial disclosures: None declared.
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Footnotes |
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2 Nonstandard abbreviations: LGMD, limb girdle muscular dystrophy; SCA, spinocerebellar ataxia; MELAS, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MERRF, myoclonic epilepsy with ragged-red fibers; NARP, neurogenic muscle weakness, ataxia and retinitis pigmentosa syndrome; CMT, Charcot-Marie-Tooth.
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References |
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