There is no formal system today for reporting and tracking laboratory errors. The lack of a formal reporting system makes it difficult to detect errors in laboratory testing, and to assess the frequency and consequences of such errors. To some extent, errors in laboratory testing, including genetic testing, are unavoidable, and the goal should be to implement systems designed to reduce errors to the extent feasible and to detect errors when they occur.
Ensuring that genetic testing is optimized to avoid error and that measures are available to detect substandard laboratory performance is of paramount importance. Equally important is providing healthcare providers and patients with sufficient information to assess the quality of genetic testing laboratories they rely on to provide critical healthcare information. Yet CMS has not provided a means for the public to access information about the quality of the laboratories it regulates, or even to determine whether a laboratory is CLIA certified.
Although a few studies previously had examined the types of laboratory errors that occur in both genetic (40) and non-genetic testing (41-44) laboratories, or have investigated adherence to professional standards (45), no prior studies had surveyed the practices of genetic testing laboratories or assessed whether the creation of a genetic testing specialty could improve testing quality.
To collect empirical data on laboratory practices and director attitudes regarding oversight, the Genetics and Public Policy Center surveyed 190 directors of molecular and biochemical genetic testing laboratories in the United States (23, 32). The survey sought information about whether laboratories were CLIA certified, were certified in a specialty area, enrolled in formal proficiency-testing programs, engaged in informal proficiency testing when formal programs were not available, had experienced deficiencies in formal proficiency testing, or had reported incorrect test results.
The survey also asked what types of errors were most frequently experienced by laboratories, and whether the laboratories complied with specific professional guidelines.
Results of the survey reveal wide variations in laboratory performance, as measured by the number of deficiencies in formal proficiency testing and the number of incorrect test results reported by the laboratory. Among the survey's findings (23):
- Many laboratories are not performing proficiency testing for all their tests. More than one-third of respondents offer some tests for which they perform no proficiency testing (Figure 2).
- Participation in proficiency testing has a clear association with laboratory quality as measured by the number of reported deficiencies in formal proficiency-testing programs. Laboratories that do not perform some type of proficiency testing on all of their tests were eight times more likely to report multiple deficiencies than laboratories that do (Figure 3).
- The number of deficiencies reported by a laboratory has a clear association with the number of reported errors. Laboratories that reported more proficiency-testing deficiencies also reported significantly higher numbers of incorrect test results. Laboratories that reported doing less proficiency testing also were more likely to report that their most common type of error is analytic.
- Even when formal proficiency-testing programs are available, some laboratories do not participate.
- When a formal proficiency-testing program is not available, laboratories do not always engage in informal proficiency testing. Twenty-three percent of respondents stated their laboratory does not always perform proficiency testing using some other mechanism when a formal proficiency-testing program is not available (Figure 4).
- Genetic testing laboratories are not always certified in other specialties. Sixteen percent of respondents reported no specialty area certification for their laboratory. Moreover, approximately one-third of both high-volume laboratories (those performing more than15,000 genetic tests per year) and those with large testing menus reported having no specialty certification.
The survey also revealed wide variation in a number of key laboratory practices, as well as practices that were inconsistent with the American College of Medical Genetics Standards and Guidelines for Clinical Genetic Laboratories (46). For example, respondents were asked whether they always include maternal cell contamination studies in prenatal testing, perform prenatal testing in duplicate, and perform DNA sequencing in both directions.
Among the findings from the survey (32):
- About 40% of respondents do not always include maternal cell contamination studies when performing prenatal testing. Thirteen percent never or hardly ever follow this practice.
- Eighteen percent of those surveyed never or hardly ever perform prenatal testing in duplicate.
- Twenty-three percent of respondents do not always sequence in both directions, and about six percent never or hardly ever do it.
Thus, in the absence of mandated standards for genetic testing laboratories, laboratories follow widely divergent practices. Although some of this variation may be appropriate given the different technologies and settings in which testing is performed, a genetic testing specialty would standardize quality control practices where appropriate and would provide the necessary enforcement mechanism to ensure that these measures were followed. These efforts would increase the quality of the tests and the medical decisions made by patients and their physicians.
Genetic testing laboratory errors can have serious consequences. Some examples are presented below.
- An Ohio woman who knew she was a carrier of an X-linked genetic disorder underwent prenatal testing to determine whether her child would inherit the disorder. She was told she would have a girl who would not have the disorder. Instead, she gave birth to a male child with serious disabilities caused by the disorder. The likely cause of this error was maternal cell contamination, in which the laboratory examined the mother's cells rather than those belonging to the fetus (35).
- A Maryland couple who both were carriers of the cystic fibrosis gene and already had an affected child sought prenatal testing to determine whether their child would have the disease. The laboratory report indicated the fetus did not have cystic fibrosis. After the child was diagnosed with cystic fibrosis at three months of age, the laboratory issued an amended report indicating that the results had been positive for the cystic fibrosis mutation. Laboratory personnel admitted they had "misread the chromatograph" indicating the genetic mutation (36).
- A young woman who experienced several episodes of deep vein thrombosis (blood clots) was tested for the factor V Leiden genetic mutation, which is associated with an increased risk of blood clots. The laboratory indicated she had the mutation. Over the course of several years, two other laboratories reported that she was negative for the mutation. Based on these reports indicating she did not have the mutation, and seeking to conceive a child, she began to take a fertility drug known to increase the risk of blood clots. Two months later she experienced extensive blood clots. A fourth genetic test indicated she had the mutation. A case report reviewing this incident determined that the woman did in fact have the mutation and cited laboratory error (sample misidentification, test failure, incorrect interpretation, or clerical error) as possible reasons for the false negative results by two of the four laboratories (37).
- A Florida couple both tested negative for the genetic mutation that causes Tay-Sachs, a fatal childhood disease. Two copies of the mutation are required to cause the disease. The couple learned that the test results were incorrect for both parents when their son began exhibiting symptoms of Tay-Sachs shortly after birth. He died eight years later (38).
- After a middle-aged man was diagnosed with a fatal adult-onset neurological disease caused by a dominant genetic mutation, three close relatives had genetic testing by a different laboratory. The laboratory, which had failed to use a sample from the affected relative for comparison, analyzed the relatives' DNA at the wrong location of the gene and issued a report to two of the relatives indicating they were negative for the mutation. Before releasing the third relative's results, the laboratory realized its error and notified the genetic counselor. The three relatives were informed of the error and decided to be re-tested. After much additional anxiety, the two relatives again tested negative, while the third relative was found to have the mutation (39).
The Genetics and Public Policy Center's survey assessed laboratory directors' attitudes toward laboratory quality and oversight. Nearly all directors found proficiency testing to be very or somewhat useful in improving the quality of genetic testing (23) (Figure 5). A majority (73%) of those surveyed agreed or strongly agreed that CLIA should create a genetic testing specialty for molecular and biochemical tests (23) (Figure 6).
While the regulated industry supports the creation of a genetic testing specialty under CLIA, the College of American Pathologists, which accredits clinical laboratories and administers proficiency testing, consistently has opposed the creation of a genetic testing specialty (47-49).
Those who have the most to gain or lose from the accuracy and reliability of genetic testing — that is, patients — resoundingly have expressed their support for the creation of a genetic testing specialty. In February 2006, the Genetic Alliance sent a letter to CMS Administrator Mark McClellan urging him to issue a proposed rule for a genetic testing specialty under CLIA, stating that a specialty "is a necessary first step toward a regulatory system that encourages new technology and ensures safety and accuracy when those technologies are implemented"(33).
A diverse array of stakeholders also has supported a genetic testing specialty under CLIA. In June 2006, a letter signed by 75 groups comprising patient advocacy organizations, genetic testing laboratories, healthcare provider organizations, and industry urged CMS to issue a proposed rule for a specialty (50). Separately, 14 women's health advocacy organizations also wrote CMS asking for creation of a genetic testing specialty (51).
Conclusion: Why a Specialty is Needed
In the 18 years since Congress enacted CLIA, genetic testing has become a critical part of clinical medicine, and among the fastest growing areas of laboratory testing (52). In that time frame, the number of genetic tests has increased more than tenfold. New companies offering genetic tests to healthcare providers and consumers appear with increasing frequency.
Yet, because of CMS's inattention and delay in implementing CLIA, neither healthcare providers nor consumers can be confident in the oversight mechanisms in place to ensure genetic tests are accurate and reliable. While genetic science and genetic technologies have leapt into the 21st century, the agency entrusted with ensuring laboratory quality is stuck in the past.
The mandate from Congress under CLIA was clear: Laboratories must participate in proficiency testing for each test they perform unless proficiency testing cannot be developed. Congress was equally clear that the absence of proficiency-testing programs or the difficulty in establishing such programs was not an adequate reason for failing to require participation in proficiency testing. Yet CMS has not mandated participation in proficiency testing for any genetic tests, nor has it demonstrated that creation of proficiency-testing programs is not possible.
Congress was similarly clear regarding the need for transparency regarding laboratory quality. To that end, the law required CMS to create a program to make the results of proficiency-testing programs available to the public. No such program has been created, nor does CMS make available to the public information on whether a laboratory is certified under CLIA. CMS could easily make this information available to healthcare providers and the public. Without this information, providers and patients are kept in the dark regarding the qualifications and competence of the laboratories that provide critical healthcare information.
To be sure, many genetic testing laboratories in the United States are of very high quality and go beyond the current minimal standards to ensure the accuracy and reliability of the genetic tests they perform. But, as the Genetics and Public Policy Center's survey of genetic testing laboratory directors reveals, some laboratories are not routinely performing proficiency testing and are not following recommended quality control procedures. Moreover, the survey indicates a correlation between proficiency testing and laboratory quality. A genetic testing specialty under CLIA would provide a mechanism for mandating both formal and informal proficiency testing. Additionally, a genetic testing specialty under CLIA would standardize quality control methods to ensure adherence to the recommended standards.
Genetic testing will have an increasing impact on public health through improved diagnosis, treatment, and prevention of disease. However, the promise of genetics to improve health and healthcare will not be realized unless genetic tests provide accurate and reliable test results. Policy to require that genetic testing be accurate and reliable has not kept pace with the growth of genetic tests. In enacting CLIA, Congress was explicit regarding the need for improved quality standards. With respect to genetic testing quality, CMS has failed to meet the expectations of Congress and the public. The creation of a genetic testing specialty is a critical first step to ensuring that laboratories have demonstrated capability to perform accurate and reliable tests. The time is now for CMS to move expeditiously to protect the public's health.
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