Adrenoleukodystrophy

REPORTS AND REVIEWS

This review article summarizes the state of the art in genetic testing and discusses the many issues that new technologies have raised. A health services perspective is offered to aid in providing laboratorians with an understanding of the dilemma that society faces with the exponential advances in knowledge. Unmistakably, these new technologies are a mixed blessing: on the one hand, diagnoses can be made with greater accuracy and preventive measures implemented more fruitfully and individuals may be more conclusively identified and/or exonerated for forensic purposes. On the other hand, however, are the very real concerns that discrimination under a medical guise will be encouraged and that privacy rights may be compromised. Another important issue is how the laboratory profession will serve in moving these new technologies from research to practice. We examine the role of the CLS in moving forward to a role of patient counselor and advocate in the emerging complex world of DNA-related biotechnology.

ABBREVIATIONS: CLS = clinical laboratory scientist

INDEX TERMS: DNA; ethics; legal; society.

Clin Lab Sci 2001;14(4):247

Over the last decade, advances in biotechnology have rendered human body fluid and tissue samples, e.g., blood, semen, amniotic fluid, saliva, skin, biopsy material, bone, and cell lines derived from them, a flash point of debate. Patient knowledge and consent is at the heart of this debate, which can be briefly characterized thusly: emerging infectious diseases such as AIDS, and the reemergence of such diseases as tuberculosis, render routine tissue sample harvesting of the utmost utility for all clinicians, clinical laboratory scientists (CLSs), and research investigators. Such samples are useful for many purposes, including, but not limited to, diagnosis, therapy, and genetic analyses.

However, due to the fact that an individual's control over their own body is the most basic foundation of any form of privacy rights, this routine harvesting raises the question of privacy rights violation. Of additional significance is the fact that the potential scientific, therapeutic, and economic importance of the information patients may provide by their body fluid and/or tissue samples is difficult, if not impossible, to ascertain in advance. It may be argued that this fact precludes any truly informed consent. Federal guidelines suggest that a patient be recontacted should a markedly different use from the ones) originally agreed to for their samples arise; this may well represent the best possible solution, if diligently applied.

PERSONAL GENETIC INFORMATION

Genetic testing encompasses the analysis of human DNA, RNA, chromosomes, proteins, and other gene products. These analyses are used to detect disease-related genotypes, mutations, karyotypes, or phenotypes as well as to aid in the definitive identification or exclusion of individuals, i.e., forensic use of genetics. The results of such analyses are applied to the prediction of disease risks, identification of carriers, monitoring, diagnosis or prognosis, and verification of genetic identity.

Any resulting genetic profile is unique to an individual, analogous to his or her fingerprints. There are an estimated 50,000 to 100,000 genes that make up the human genome, and when researchers have identified the sequence of each gene, it is thought that the function will be able to be elucidated in relatively short order.2 This unique human blueprint offers many potential applications for use and misuse. One positive use of personal genetic information is clearly in fighting complex multifactorial diseases such as cancer and mental illness, but also such devastating metabolic conditions, e.g., adrenoleukodystrophy, that are attributable to derangements in a single gene. Recombinant DNA techniques developed in the past two decades have permitted the discovery of genes which, when altered by germline or somatic mutations, increase the risk of disease or result in a disease state. Such findings may lead to the development of genetic tests for disease-causing alleles for single-- gene Mendelian disorders and susceptibility-conferring alleles for polygenic disorders.

Other uses of tissue and body fluid samples that are generally regarded as societally positive include the data banks maintained by the Federal Bureau of Investigation (FBI), the armed services, and state governments. Most typical uses of these banks are to identify criminals and missing persons. Indeed, most commentators have traditionally defined a DNA databank as `an entity that stores human DNA and/or genetic records for law enforcement purposes'.3 Such banks may include actual tissue samples or coded genetic information. Several states. e.g., New Mexico, Alabama, and Virginia, routinely collect DNA information for every felony conviction; in others, e.g., Connecticut, such legislation is being considered. In addition to any DNA information on file, most such data banks also contain computerized records intended to help identify individuals, with such physical or phenotypic characteristics as weight, height, hair color, eye color, skin marks, and fingerprint patterns.

In general, there are four kinds of organizations that bank DNA data.4 In addition to the forensic banks and the military, commercial laboratories bank DNA, as do university-based repositories for research. These latter two groups have not engendered as much controversy as the military and the government's forensic use of data, but concerns are still raised as to the use and eventual disposition of the information that these organizations store. Since many of the samples collected by universities and commercial enterprises are donated voluntarily, the potential element of civil rights violations is rendered somewhat less salient.

PRE- AND ANTENATAL SCREENING

In a typical newborn metabolic screening program, inexpensive and efficient assays are used to screen for disorders such as hypothyroidism, phenylketonuria, galactosemia, and hemoglobinopathies. These screening programs use different methodologies, e.g., microbiological, biochemical, radioimmunoassay, for early detection and diagnosis. Such detection is essential to implement dietary and other interventions that can significantly reduce the effects of any diseases detected. They may also prolong life, in severe instances, or ameliorate the often devastating effects of nonintervention, e.g., severe mental retardation in phenylketonuria.

The success of these types of screening programs has been documented using well-recognized health services outcomes indicators.5,6 As part of the routine processing of newborn screening procedures, specimens, such as filter paper blots, are stored for future retesting if necessary. State laws and informed consent allow for the testing and storage of such specimens. However, these stored specimens contain DNA and limited legislation exists addressing the use of such materials for genetic testing. To complicate the issue, informed consent has rarely been obtained to use these tissues for genetics testing either in a diagnostic capacity or for research.

The area of prenatal or newborn screening is yet another area where patient education and counseling is needed. Pre- and antenatal diagnostics and testing is an area fraught with concerns for consumers.

PLACENTAL BLOOD FOR TRANSPLANTATION

For-profit enterprises have typically dominated this endeavor, lending a unique dimension to ethical concerns. In 1997, the Journal of the American Medical Association published a report by the Working Group on Ethical Issues in Umbilical Cord Blood Banking. The following issues were identified, among others, as essential elements to be considered: "marketing practices for UCB (umbilical cord blood) banking in the private sector need close attention; ...more data are needed to ensure that recruitment for banking and use of UCB are equitable; and ...the process of obtaining informed consent for collection of UCB should begin before labor and delivery.7

Some nonprofit cord blood banks do exist, but they are currently outnumbered by the for-profit banks. These banks are maintained for all those in need, not to store blood for any particular potential recipient. As the for-profit blood banks offer a service that only the financially fairly well off individuals can afford, the initial costs range from $500 to $1000, plus an annual storage fee of about $100, the benefits of banking are denied to economically disadvantaged families.

The issue of interest to the laboratory profession arises from the question of whether cord blood stem cells will be considered a therapeutic/pharmaceutical product or if they will be classified as blood banking products and be dispensed accordingly. As the advances in stem cell transplantation technology increase, it is likely to change the way in which stem cells are utilized by the medical community. The day that stem cells are used on a regular basis to treat, e.g., childhood leukemias, may not be too far distant. The profession would do well to inform itself now of the potential ramifications of noninvolvement in the control and use of the product.

SCREENING FOR GENETIC SUSCEPTIBILITY TO DISEASE: AN OPPORTUNITY TO SERVE

Genetic screening has long been a goal of clinicians and scientists. Due to advances in biotechnology, genetic screening for susceptibility to diseases such as cardiovascular disease, diabetes, and some cancers appears to be on the horizon. Many types of disease are believed to stem from the interaction of multiple genes, each playing a minor contributory role, with environmental factors playing a major role.8 Dissection of predisposing genetic factors for common, multifactorial disorders may lead to a new paradigm in healthcare delivery. Some writers believe, perhaps disingenuously, that individuals identified as being at risk for certain diseases will be able and motivated to alter their lifestyles in a manner that minimizes the risk of disease manifestation or progression.9 Others fear that punitive insurance rates would preclude medical assistance to such individuals and create a new underclass of individuals who may face discrimination in the workplace and elsewhere.

As with prenatal diagnostics and screening, discussed above, this type of service is one that could very beneficially be established in settings such as the neighborhood clinics, where community members already feel at home.

CRIMINAL DATABASES

As part of the 1994 Crime Bill, the FBI was enabled by the DNA Identification Act of 1994, 42 U.S.C. (sec)14132(10) to "establish an index of. 1) DNA identification records of persons convicted of crimes; 2) analyses of DNA samples recovered from crime scenes; and 3) analyses of DNA samples recovered from unidentified human remains".

In response, the FBI has created a database called the Combined DNA Index System (CODIS) for law enforcement identification purposes. CODIS is a computer database of DNA profiles stored in three indexes: convicted offenders, unknown suspects, and population samples for statistical purposes. Using the CODIS, law enforcement agencies at the federal, state, and local levels can search DNA samples to seek a match with the database. As of October 1998, CODIS had been installed in over 90 laboratories in 41 states and the District of Columbia. This is a multi-tiered system, which consists of local, state, and national levels.

Because many people have privacy concerns relating to giving such a sample, but also have an inclination to assist law enforcement, the laboratory can play a role here as well. The police may permit individuals in a community to donate DNA samples at their local laboratory, thereby maximizing compliance and assuring that the procedures are conducted safely and efficaciously. The CLS could provide the necessary counseling and education to the patient before collecting the DNA samples. The samples would then be submitted to the appropriate repository. A TICKING TIME BOMB: DISEASE SUSCEPTIBILITY GENES

Cancer

Information as to one's likelihood of developing cancer is one of the most important advances that medical science can offer society. Although hereditary cancers are a small percentage of total cancers, significant advances have been made in understanding the genetic basis of those that are known. To take a well-known example, a majority, about 70%, of hereditary breast and ovarian cancers are attributable to mutations in the BRCAI and BRCA2 genes. Women with a mutation in either gene have an increased chance (50% by age 45 and about 85% overall) of developing breast cancer, and an increased lifetime risk (at least 15% to 20%) of ovarian cancer; men with the gene have a higher risk of prostate cancer.11

Disturbingly typical for such emerging technologies, testing has outpaced potential prophylaxes or treatments. Currently, women are given an extremely limited range of options for prophylactic treatment once they are found to have a mutation. Bilateral mastectomies or ovariectomy are recommended preventative measures, neither of which is a complete barrier to cancer development. A recent study in the New England Journal of Medicine indicates that the mastectomy option may substantially improve survival, while ovariectomy seems to, at best, add length to life without impacting cancer incidence.12 A recent study further found that oral contraceptives decrease the risk of ovarian cancer in BRCA mutation carriers.13 However, the likelihood of an insurer covering such testing and/or prophylaxis is uncertain, potentially leading to discrepancies in cancer survival rates between those that can afford these measures and those that cannot. In response to this problem, Myriad Genetics-the supplier of the BRCA tests in the majority of cases-has entered into agreements with 11 companies which do cover the cost of the testing-usually about $2,000.

Huntington's Disease and other genetic maladies

In contrast to the uncertainties regarding cancer outcome based on mutational status, the test for Huntington's Disease (HD) provides somewhat more certainty regarding the fate of the affected individual. Basically, an expansion of the trinucleotide repeat CAG is seen in all gene copies, but the number of repeats seems to determine the presence and severity of the illness. Most normal individuals have between 18 to 29 repeats; generally with less than 30 repeats, they will not develop HD. With over 40 repeats the likelihood of the disease appearing becomes virtually certain, with earlier age of onset being correlated with higher number of repeats. There is a gray area of 30 to 40 repeats, where it is uncertain whether a person will develop the disease or not.14 This trinucleotide expansion motif is also seen in other types of neurodegenerative genetic diseases, e.g., Friedrich's and spinocerebellar ataxias, myotonic dystrophy, and fragile X syndrome.

Additionally, genetic tests are available commercially for the thalassemias, various neurodegenerative diseases, and endocrine dysfunctions such as Angelman and Prader-Willi syndromes. Again, approaches to coping with the consequences of finding out about one's status or the likely or certain status of one's child lag behind the genetic technology.

As genetic tests evolve and their acceptance is more widespread, one appropriate venue for their implementation would be the laboratory. CLSs have the opportunity to develop their own databases from their contacts with patients. These databases could guide them in deciding which patients could benefit from testing and would also aid in providing referrals for appropriate counseling.

PUBLIC PERCEPTIONS REGARDING GENETIC INFORMATION AND USES THEREOF

A 1995 Harris poll found that 85% of the individuals surveyed stated a concern regarding the use of personal genetic information by employers and insurers. Earlier, in 1992, a March of Dimes poll found a somewhat more cavalier attitude towards the privacy rights of other people. The majority of individuals polled (57%) thought that someone other than the patient should have the right to know if that person is a carrier for a defective gene. Of that 57%, 98% stated that a spouse/fiance(e) had the right to know, but 58% believed insurance companies should know, and 33% stated that an employer should be told.

The laboratory profession can and should assist in the process of dispelling myths and easing fears. Combating the enemy of ignorance might well begin with the CLS. Initiatives such as that by the American Association for the Advancement of Science regarding new genetic technologies might do well to target the CLS as a contact for the interested layperson.

MEDICAL PRIVACY, GENETIC DISCRIMINATION, AND OTHER LEGAL ISSUES: WHAT EVERY CLS SHOULD KNOW

Federal Laws

One means of attempting to address the concerns of the public that insurers or employers may find out their genetic status and misuse this information might be via federal legislation. The 1996 Health Insurance Portability and Accountability Act (HIPAA) is the only federal law to directly address potential discrimination on a genetic basis by insurers. It seeks to bar group health plans from utilizing any health information, including genetic, as a means of denying or limiting coverage or increasing an individual's cost of insurance. As might be expected, multiple additional federal and state legislation is pending.

Another potential defense against `genetic discrimination' might be the Americans with Disabilities Act (ADA) and similar legislation, e.g., the Rehabilitation Act of 1973. Although some have read the ADA to confer protection to those individuals with a predisposition to cancer, the Act in its strictest sense provides protection only for those individuals with a currently symptomatic genetic disease. Hence, carriers or persons with a higher probability of succumbing to a disease are not shielded by ADA. The Equal Employment Opportunity Commission (EEOC) has attempted to fill this gap by trying to extend application of the ADA to employers who might take action against a worker based on genetic information. However, this is merely policy guidance, and is not legally binding.

On the state level, laws that specifically protect individuals from employment or insurance discrimination due to undergoing genetic testing or being found to carry a mutation have been passed in at least 11 states.

OWNERSHIP OF GENES/CELL LINES

One thorny issue that arises out of the existence of data banks of genetic material (or blood or other body substances), is whether persons actually have property rights in their cell lines, body fluids, or genes. Traditionally, in terms of the sale of plasma or semen, these processes have been termed services, not sales, since body parts are not considered property. It is important to place this issue in some kind of legalistic context, so that the CLS may be informed as to the current state of the art, with the caveat that the courts may change the status of the current law at any time.

The case of Moore vs. Regents of the University of California brought the question of who owns a patient's cells directly into the spotlight at the end of the 1980s.15 Briefly, John Moore was a patient with hairy cell leukemia, from whose body fluids, tissues, and spleen a scientifically interesting and potentially valuable cell line was isolated by his physician, without his knowledge or consent. The physician never informed Moore of the value of his cells, leading him to believe that multiple visits to harvest cells were in fact medically necessary. Mr. Moore sued multiple defendants on multiple counts but prevailed only on the issue that he should have been informed of the potential conflict of interest his physician had when the unique properties of his cells were first established, premised on the fiduciary relationship between Moore and his doctor.

This case has engendered much commentary in legal circles. Foremost has been the issue of whether or not we as a society must redefine property to include genetic material.3,16-18 The bias has been against considering body parts as property, ostensibly on public policy grounds, in order to prevent such consequences as sale of body parts by the economically desperate. However, given the unique status of cell lines and genes, and their potential for generating profits for mankind, both economic and in terms of future medical knowledge, it may be time to rethink the definition of 'property'. What the metes and bounds of such a new definition might be, however, remains unclear.

Further, there has been extensive legal commentary regarding the overall issue of the unique nature of genetic material within the realm of privacy rights/discrimination, especially by insurers.18 This commentary provides an interesting summary of these issues, emphasizing the unique features of DNA from a policy analysis standpoint. They argue that DNA is unique in the information it provides for five reasons: three relating to the intrinsic nature of the molecule (its information-rich aspect, its longevity, and its role as an identifier) and the risks its information poses to families and the impacts this information can have on communities.

Federal guidelines attempt to provide some assistance here. The Presidents Commission For The Study Of Ethical Problems In Medicine And Biomedical And Behavioral Research Screening And Counseling For Genetic Conditions has offered guidelines for dealing with the issue of when confidential medical information should be disclosed to others only under the following conditions: 1) "reasonable attempts to elicit voluntary disclosure are unsuccessful; 2) there is a very high probability of very serious harm; 3) there is reason to believe disclosure will prevent the harm; and 4) disclosure is limited to the information necessary for diagnosis or treatment of another person."

It has been commented that the United States needs federal legislation that would ensure "...[D]onor confidentiality, donor access to genetic material and test results, and recognizing property rights in donated human tissue and DNA."3 This may be one means of providing needed protection for those individuals whose rights to privacy may be invaded by biotechnology. There remain special considerations for special populations, e.g., the institutionalized, prisoners, etc.

THE ROLE OF INSTITUTIONAL REVIEW BOARDS

Institutional Review Boards (IRBs) are charged with protecting human subjects during the research process. Basic research, clinical trials, and interventions of drugs and medical devices require that investigators secure IRB approval from their institution prior to conducting any research involving humans or animals. However, IRBs only monitor drugs and devices during the research process. Once approved by the Food and Drug Administration, appropriate use of the drug or device is up to the practitioner.

IRBs are very involved in monitoring genetic research and many members of these Boards have expressed concern over the lack of policy to guide the use of these findings once they become available commercially. Ethical issues surround the unintended uses of this research. A major concern is who is to dispense genetic materials. Will it be considered a pharmaceutical product that requires a prescription and will be dispensed by a pharmacy or will it be available directly to physicians via the laboratory? Is there a need for the laboratory to develop a specialty and new guidelines to handle this product or will current state laws and evolving procedures provide sufficient protective measures? These are all questions that have to be answered in the near future. Policies are needed to provide guidance in the development of these new services to minimize misuse and litigation involving these products.

A sidenote on the issue of vaccines: Since 1986, claims arising in vaccine litigation have been capped by federal statute. Designed to avoid excessive liability burdens on companies developing and manufacturing vaccines, the federal Vaccine Injury Compensation Program has established a compensation system to adjudicate claims arising from injuries and deaths allegedly attributable to standard vaccines. That many states now permit various health professionals to administer vaccines is a clear step in the direction the authors advocate, namely that CLSs be given wider healthcare roles in order to better serve their patients.

RESEARCH ON STORED TISSUES

The general policy concerning research on stored tissues, including blood, saliva and other body fluids, is to require informed consent while the individual from whom the tissue came is still alive. If the individual is dead, or if the tissue donor cannot be identified, then federal regulations generally permit use of tissue samples, except when genetic research may uncover information that could pose risks to living relatives. In such a case, the relatives may deny the use of the sample, unless the decedent had explicitly consented to the research before death.

However, investigators are generally permitted to 'anonymize' tissue samples by removing identifiers, thus obviating informed consent provisions. This is important for the CLS to understand, in order to better inform patients who might be concerned about such end-of-life issues.

CONCLUSION

Clearly, we are moving into an era of increasingly complicated bioethical issues. It is not possible to turn the clock back on technical advances, nor is it possible for well-meaning scientific mandates to dictate the values of the marketplace. The numerous scientific advances will create a sizable marketplace that the current healthcare structure is not prepared to handle. The CLS can and should play a pivotal role in developing policies with other colleagues that will guide patients through the labyrinth of technology as an essential member of the disease management team. It is the experience of the profession that is needed in policy development to pave the road for the individual CLS to fill this role.

ACKNOWLEDGEMENTS

This research was supported by the National Institute on Drug Abuse (NIDA grant # DA11414). The authors would like to thank Anita Goodly for her assistance with the manuscript. Opinions expressed herein are solely those of the authors.

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14. Kremer B, Goldberg PI Andrew SE, and others. A worldwide study of the Huntington's Disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med 1994;330:1401-6.

15. Moore vs. the Regents of the University of California, 215 Cal. App 3' 709.

16. Perley SN. Note: from control over one's body to control over one's body parts: extending the doctrine of informed consent. New York University Law Review 1992;67:335-65.

17. Wozniak FJ. Annotation: physician's use of patient's tissues, cells or bodily substances for medical research or economic purposes. ALR 5' 1996;16:143-7.

18. Green RM, Thomas AM. DNA: five distinguishing features for policy analy

sis. Harvard J Law Tech 1998;11:571-90.

Heidi M Struse PhD is a Research Scientist at Affiliated Systems Corporation, Houston TX.

Isaac D Montoya PhD CMC CLS is a Senior Research Scientist at Affiliated Systems and a Clinical Professor in the College of Pharmacy at the University of Houston, Houston TX.

Address for correspondence: Dr Isaac D Montoya, Affiliated Systems Corporation, 3104 Edloe, Suite 330, Houston TX 77027-6022.

imontoya@affiliatedsystems.com

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