Letters to the Editor
Am. J. Hum. Genet. 50:643-645, 1992
Threatened Survival of Academic-based Genetic Laboratory Services To the Editor: The enormous advances in human genetics have largely originated in the laboratories of academic institutions, often as a consequence of interactive collaboration between basic scientists and clinical geneticists. Endless achievements exist and include: cystic fibrosis,
thalassemia, the fragile-X syndrome, Huntington disease and Duchenne/Becker muscular dystrophy. More commonplace, perhaps, are the clinical cytogenetic advances, as well as pregnancy screening for neural tube and chromosome defects. Clinical case-based major epidemiological studies have also resulted in significant contributions. These developments, with expedited technology transfer benefiting much larger numbers of patients, have been associated with a vast increase in genetic testing. Many of these advances came to fruition in the deregulated business atmosphere created by the Reagan administration. Simultaneously, academicians experienced increasing difficulty in obtaining funding. Consequently, individuals, divisions, departments, and institutions recognized alternative financial pathways. Some geneticists, leaving academe (and taking their laboratories with them), became businessmen, while others became wholly or significantly dependent upon laboratory service income for their own and their staff support. The free marketeers were quick to realize potential profit centers, and the expected cascade of older and newer start-up companies entered the genetic testing marketplace with vigor. Indeed, the pur-
chase of entire academic service laboratories by commercial companies is in full swing. These companies, with their large advertising budgets, often unscrupulous sales representatives, and, not infrequent unethical business practices, have invaded the academic institutional genetic laboratory marketplace. As a consequence, many such units have (or will) experience significant losses of their regular referral sources and have begun to recognize a clear and evident threat to their actual survival. Clinical geneticists, genetic counselors, and Ph.D. medical and laboratory-based geneticists face salary cuts and, ultimately, job loss. The advent of commercial genetic laboratory diagnostic services has not yet reached a crescendo but is steadily moving in that direction. This is a most serious development with direct implications for human genetics research, teaching, and clinical and laboratory training. A diminishing sample and patient load has directly impacted (and will continue to impact) the teaching of medical students and postdoctoral M.D. and Ph.D. fellows in clinical cytogenetics, biochemical genetics, and molecular genetics. The clinical training of medical students, residents, and postdoctoral M.D. or Ph.D. fellows who need to fulfill ABMG requirements has begun to suffer and will continue to suffer. A similar fate is likely for the required ABMG training of genetic counselors and will also involve social workers and nurses in genetics, as well as other ancillary health professionals. The laboratory training of Ph.D's in clinical cytogenetics and biochemical and molecular genetics is also seriously threatened. 643
644
The complex nature of genetic testing and the sophisticated knowledge required for interpretation make commercial laboratories a poor choice for such studies. Important lessons were learned in the California newborn phenylketonuria screening program at a time when assays were allowed in many locations. Repeated laboratory and program errors resulted in a number of infants with phenylketonuria being missed and subsequently found to be mentally retarded (Committee for the Study of Inborn Errors of Metabolism 1975). Molecular genetic diagnosis, analysis for presymptomatic carriers, or prenatal detection can be complicated enough for the clinical geneticist and is clearly beyond the training of other physicians who request such studies directly from commercial laboratories and proceed to interpret the reports. One especially painful and poignant example is the remarkable case of Patricia Stallings of St. Louis. She had been convicted for the murder of her 5-mo-old son, allegedly with ethylene glycol (antifreeze) and had been sentenced to life imprisonment. In prison she delivered a second son, who was diagnosed with methylmalonic acidemia. Serum samples from her first son were recovered, reassayed, and methylmalonic acid - not ethylene glycol was detected! A large commercial laboratory had performed the first assay. Ms. Stallings, on retrial, was cleared of all criminal charges. Increasingly sophisticated chromosome analyses also require in-depth knowledge. Maternal serum screening for neural tube and chromosome defects are undoubtedly best provided in a comprehensive setting where there is direct proximate involvement of a clinical geneticist with the screening laboratory, ultrasonography, and obstetric services (Milunsky and Alpert 1978). All these diagnostic and screening services require direct involvement of physicians trained in clinical genetics who understand the intricacies of patient communications. Some commercial laboratories are providing medical advice and are further inviting direct liability by sending genetic counselors with a master's degree into doctors' offices to provide genetic counseling. I am concerned for these counselors. These circumstances represent the practice of medicine without a license, and genetic counselors and the physicians' offices they visit should both be appraised of their considerable personal liability. The not unexpected excesses of commercialization have already become apparent. Company claims of new, more accurate screening or diagnostic tests have begun to flood the mail. The need for scientific confirmation, peer review, prior publication, FDA approval, licensing, or clinical trials has not daunted companies from making such claims. Where are those
Letters to the Editor
responsible for regulatory affairs, licensing, oversight, and quality control? Commercial laboratories who profit from their developments would be considered less than proper locations for confirming the validity of any claims made. The ASHG clearly needs to formulate some policy governing the rampant commercialism, which was quite evident at the recent 8th International Congress of Human Genetics. Directors of genetics departments, divisions, service laboratories, and training programs now need to recognize the evident threat to their academic establishment and take protective steps. I can suggest a few, and perhaps others will share their ideas in the Journal. 1. Inform and direct your own staff to send diagnostic/screening samples only to academic service laboratories. 2. Educate the referring physicians about the wisdom of formal and comprehensive services for their patients, over the services of isolated commercial laboratories. 3. Improve your own services to match those of industry. 4. Do not support commercial operations by providing them with academic linkage. This type of association is used by their sales representatives (by name-dropping) to further influence referral sources away from your own or other academic facilities. 5. Call attention to the appropriate agencies when unethical or improper business practices are encountered. 6. Join the interacademic genetic laboratory referral network established by the undersigned to facilitate referrals between academic centers. A directory listing available tests and specific disorders, updated annually, will be provided to each participating academic center. A free society needs all the capitalists it can attract and deserves the consequences of their unfettered and uncontrolled activities. The hopes and aspirations of academic geneticists are not in synchrony with the financial profit goals of commercial laboratories. A stark reminder to me was the large color poster at the entrance of one large genetics service laboratory detailing "sales achievements." Those "achievements" directly threaten the survival of academic geneticbased service laboratories. AUBREY MILUNSKY Center for Human Genetics Boston University School of Medicine
Letters to the Editor References Committee for the Study of Inborn Errors of Metabolism (1975) Genetic screening: programs, principles, and research. National Academy of Sciences, Washington, DC Milunsky A, Alpert E (1978) Maternal serum AFP screening. N Engl J Med 298:738-739 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5003-0026$02.00
Am. J. Hum. Genet. 50:645-646, 1992
Segregation Analysis in Alzheimer Disease: No Evidence for a Major Gene To the Editor: There is a general agreement to say that, in some multiple-case families, Alzheimer disease (AD) is very likely to be of genetic origin. In those families the disease onset is usually early, and the transmission pattern suggests an autosomal dominant mode of inheritance. Furthermore, there is some evidence that a disease-causing gene is on chromosome 21, although one recent linkage study has failed to locate it precisely (St George Hyslop et al. 1990). However, the origin of the great majority of AD cases -in particular those with a late onset -remains very controversial, and, although the single-gene hypothesis with no sporadic cases is attractive because of its simplicity, it is by no means certain. Under this hypothesis, the absence of familial clustering in most AD cases would be explained by the censoring bias due to the late onset of the disease: most of the unaffected gene carriers in a family would have died of a competing risk prior to the age at onset. Other hypotheses have been proposed -e.g., a second locus, on chromosome 21, for susceptibility to AD; a locus on chromosome 19; nongenetic factors; or the interaction of multiple genetic and environmental factors but none is yet conclusive. In this context, segregation analysis is of major interest, as it can help to gauge the likelihood of these hypotheses (Morton and MacLean 1974). It is surprising that very few segregation analyses of AD had been published, until the paper by Farrer et al. (1991) in a recent issue of the Journal. The authors performed a segregation analysis, with a correction of censoring bias due to age, on 232 nuclear families ascertained
645
through a memory disorder unit. Their conclusion is that in AD there is some evidence for a major gene associated with a multifactorial component. However, although the authors referred to the original paper of Morton and MacLean (1974), they incorrectly used the mixed model in their model comparisons. Indeed, to assess the likelihood of the transmission of a major gene, the authors compared the multifactorial model (Farrer et al. 1991, model 2 in table 3) with the mixed model with unrestricted d and r's (Farrer et al. 1991, model 13 in table 3), which is in fact the unified model proposed by Lalouel et al. (1983). The likelihood-ratio (x2) test between these models was highly significant (X6 = 13.27, P< .001), and the hypothesis of the absence of a major-locuscomponent transmission of AD was rejected by the authors. As a matter of fact, the mixed model, as defined by Morton and MacLean, is model 12 (Farrer et al. 1991, table 3) with transmission probabilities constrained to their Mendelian values. The likelihood-ratio (X2) test between this model and the multifactorial model is not significant (X3 = 5.56, P = .135). This means that the hypothesis of the absence of a major-locus-component transmission of AD is not rejected. Conversely, the multifactorial component is highly significant (model 7 vs. model 12; X2 = 15.68, P< .001). In the absence of any evidence for a major gene in AD, there is no indication to test other hypotheses -in particular the Mendelian T's - and the model that best explains these data is the multifactorial model. This conclusion was already reached by MacGuffin et al. (1991) in a previous segregation analysis, but it does not prove that a major gene could not be involved in AD etiology: the impossibility of detecting its presence could be due to a lack of power in the analyses. However, the impossibility of finding a major-gene effect in a large-scale, censoring-corrected, segregation-analysis study suggests that this effect would be responsible only for a very few cases and that most AD cases are of a multifactorial origin. C. TzoURIO,* C. BONAITI4 F. CLERGET-DARPOUX,t AND A. ALPEROVITCH*
*National Institute of Health and Medical Research (INSERM) U169 Villejuif and tINSERM U155 Longchamp, France References Farrer LA, Myers RH, Connor L, Cupples LA, Growdon JH (1991) Segregation analysis reveals evidence of a major
Am. J. Hum. Genet. 50:643-645, 1992
Threatened Survival of Academic-based Genetic Laboratory Services To the Editor: The enormous advances in human genetics have largely originated in the laboratories of academic institutions, often as a consequence of interactive collaboration between basic scientists and clinical geneticists. Endless achievements exist and include: cystic fibrosis,
thalassemia, the fragile-X syndrome, Huntington disease and Duchenne/Becker muscular dystrophy. More commonplace, perhaps, are the clinical cytogenetic advances, as well as pregnancy screening for neural tube and chromosome defects. Clinical case-based major epidemiological studies have also resulted in significant contributions. These developments, with expedited technology transfer benefiting much larger numbers of patients, have been associated with a vast increase in genetic testing. Many of these advances came to fruition in the deregulated business atmosphere created by the Reagan administration. Simultaneously, academicians experienced increasing difficulty in obtaining funding. Consequently, individuals, divisions, departments, and institutions recognized alternative financial pathways. Some geneticists, leaving academe (and taking their laboratories with them), became businessmen, while others became wholly or significantly dependent upon laboratory service income for their own and their staff support. The free marketeers were quick to realize potential profit centers, and the expected cascade of older and newer start-up companies entered the genetic testing marketplace with vigor. Indeed, the pur-
chase of entire academic service laboratories by commercial companies is in full swing. These companies, with their large advertising budgets, often unscrupulous sales representatives, and, not infrequent unethical business practices, have invaded the academic institutional genetic laboratory marketplace. As a consequence, many such units have (or will) experience significant losses of their regular referral sources and have begun to recognize a clear and evident threat to their actual survival. Clinical geneticists, genetic counselors, and Ph.D. medical and laboratory-based geneticists face salary cuts and, ultimately, job loss. The advent of commercial genetic laboratory diagnostic services has not yet reached a crescendo but is steadily moving in that direction. This is a most serious development with direct implications for human genetics research, teaching, and clinical and laboratory training. A diminishing sample and patient load has directly impacted (and will continue to impact) the teaching of medical students and postdoctoral M.D. and Ph.D. fellows in clinical cytogenetics, biochemical genetics, and molecular genetics. The clinical training of medical students, residents, and postdoctoral M.D. or Ph.D. fellows who need to fulfill ABMG requirements has begun to suffer and will continue to suffer. A similar fate is likely for the required ABMG training of genetic counselors and will also involve social workers and nurses in genetics, as well as other ancillary health professionals. The laboratory training of Ph.D's in clinical cytogenetics and biochemical and molecular genetics is also seriously threatened. 643
644
The complex nature of genetic testing and the sophisticated knowledge required for interpretation make commercial laboratories a poor choice for such studies. Important lessons were learned in the California newborn phenylketonuria screening program at a time when assays were allowed in many locations. Repeated laboratory and program errors resulted in a number of infants with phenylketonuria being missed and subsequently found to be mentally retarded (Committee for the Study of Inborn Errors of Metabolism 1975). Molecular genetic diagnosis, analysis for presymptomatic carriers, or prenatal detection can be complicated enough for the clinical geneticist and is clearly beyond the training of other physicians who request such studies directly from commercial laboratories and proceed to interpret the reports. One especially painful and poignant example is the remarkable case of Patricia Stallings of St. Louis. She had been convicted for the murder of her 5-mo-old son, allegedly with ethylene glycol (antifreeze) and had been sentenced to life imprisonment. In prison she delivered a second son, who was diagnosed with methylmalonic acidemia. Serum samples from her first son were recovered, reassayed, and methylmalonic acid - not ethylene glycol was detected! A large commercial laboratory had performed the first assay. Ms. Stallings, on retrial, was cleared of all criminal charges. Increasingly sophisticated chromosome analyses also require in-depth knowledge. Maternal serum screening for neural tube and chromosome defects are undoubtedly best provided in a comprehensive setting where there is direct proximate involvement of a clinical geneticist with the screening laboratory, ultrasonography, and obstetric services (Milunsky and Alpert 1978). All these diagnostic and screening services require direct involvement of physicians trained in clinical genetics who understand the intricacies of patient communications. Some commercial laboratories are providing medical advice and are further inviting direct liability by sending genetic counselors with a master's degree into doctors' offices to provide genetic counseling. I am concerned for these counselors. These circumstances represent the practice of medicine without a license, and genetic counselors and the physicians' offices they visit should both be appraised of their considerable personal liability. The not unexpected excesses of commercialization have already become apparent. Company claims of new, more accurate screening or diagnostic tests have begun to flood the mail. The need for scientific confirmation, peer review, prior publication, FDA approval, licensing, or clinical trials has not daunted companies from making such claims. Where are those
Letters to the Editor
responsible for regulatory affairs, licensing, oversight, and quality control? Commercial laboratories who profit from their developments would be considered less than proper locations for confirming the validity of any claims made. The ASHG clearly needs to formulate some policy governing the rampant commercialism, which was quite evident at the recent 8th International Congress of Human Genetics. Directors of genetics departments, divisions, service laboratories, and training programs now need to recognize the evident threat to their academic establishment and take protective steps. I can suggest a few, and perhaps others will share their ideas in the Journal. 1. Inform and direct your own staff to send diagnostic/screening samples only to academic service laboratories. 2. Educate the referring physicians about the wisdom of formal and comprehensive services for their patients, over the services of isolated commercial laboratories. 3. Improve your own services to match those of industry. 4. Do not support commercial operations by providing them with academic linkage. This type of association is used by their sales representatives (by name-dropping) to further influence referral sources away from your own or other academic facilities. 5. Call attention to the appropriate agencies when unethical or improper business practices are encountered. 6. Join the interacademic genetic laboratory referral network established by the undersigned to facilitate referrals between academic centers. A directory listing available tests and specific disorders, updated annually, will be provided to each participating academic center. A free society needs all the capitalists it can attract and deserves the consequences of their unfettered and uncontrolled activities. The hopes and aspirations of academic geneticists are not in synchrony with the financial profit goals of commercial laboratories. A stark reminder to me was the large color poster at the entrance of one large genetics service laboratory detailing "sales achievements." Those "achievements" directly threaten the survival of academic geneticbased service laboratories. AUBREY MILUNSKY Center for Human Genetics Boston University School of Medicine
Letters to the Editor References Committee for the Study of Inborn Errors of Metabolism (1975) Genetic screening: programs, principles, and research. National Academy of Sciences, Washington, DC Milunsky A, Alpert E (1978) Maternal serum AFP screening. N Engl J Med 298:738-739 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5003-0026$02.00
Am. J. Hum. Genet. 50:645-646, 1992
Segregation Analysis in Alzheimer Disease: No Evidence for a Major Gene To the Editor: There is a general agreement to say that, in some multiple-case families, Alzheimer disease (AD) is very likely to be of genetic origin. In those families the disease onset is usually early, and the transmission pattern suggests an autosomal dominant mode of inheritance. Furthermore, there is some evidence that a disease-causing gene is on chromosome 21, although one recent linkage study has failed to locate it precisely (St George Hyslop et al. 1990). However, the origin of the great majority of AD cases -in particular those with a late onset -remains very controversial, and, although the single-gene hypothesis with no sporadic cases is attractive because of its simplicity, it is by no means certain. Under this hypothesis, the absence of familial clustering in most AD cases would be explained by the censoring bias due to the late onset of the disease: most of the unaffected gene carriers in a family would have died of a competing risk prior to the age at onset. Other hypotheses have been proposed -e.g., a second locus, on chromosome 21, for susceptibility to AD; a locus on chromosome 19; nongenetic factors; or the interaction of multiple genetic and environmental factors but none is yet conclusive. In this context, segregation analysis is of major interest, as it can help to gauge the likelihood of these hypotheses (Morton and MacLean 1974). It is surprising that very few segregation analyses of AD had been published, until the paper by Farrer et al. (1991) in a recent issue of the Journal. The authors performed a segregation analysis, with a correction of censoring bias due to age, on 232 nuclear families ascertained
645
through a memory disorder unit. Their conclusion is that in AD there is some evidence for a major gene associated with a multifactorial component. However, although the authors referred to the original paper of Morton and MacLean (1974), they incorrectly used the mixed model in their model comparisons. Indeed, to assess the likelihood of the transmission of a major gene, the authors compared the multifactorial model (Farrer et al. 1991, model 2 in table 3) with the mixed model with unrestricted d and r's (Farrer et al. 1991, model 13 in table 3), which is in fact the unified model proposed by Lalouel et al. (1983). The likelihood-ratio (x2) test between these models was highly significant (X6 = 13.27, P< .001), and the hypothesis of the absence of a major-locuscomponent transmission of AD was rejected by the authors. As a matter of fact, the mixed model, as defined by Morton and MacLean, is model 12 (Farrer et al. 1991, table 3) with transmission probabilities constrained to their Mendelian values. The likelihood-ratio (X2) test between this model and the multifactorial model is not significant (X3 = 5.56, P = .135). This means that the hypothesis of the absence of a major-locus-component transmission of AD is not rejected. Conversely, the multifactorial component is highly significant (model 7 vs. model 12; X2 = 15.68, P< .001). In the absence of any evidence for a major gene in AD, there is no indication to test other hypotheses -in particular the Mendelian T's - and the model that best explains these data is the multifactorial model. This conclusion was already reached by MacGuffin et al. (1991) in a previous segregation analysis, but it does not prove that a major gene could not be involved in AD etiology: the impossibility of detecting its presence could be due to a lack of power in the analyses. However, the impossibility of finding a major-gene effect in a large-scale, censoring-corrected, segregation-analysis study suggests that this effect would be responsible only for a very few cases and that most AD cases are of a multifactorial origin. C. TzoURIO,* C. BONAITI4 F. CLERGET-DARPOUX,t AND A. ALPEROVITCH*
*National Institute of Health and Medical Research (INSERM) U169 Villejuif and tINSERM U155 Longchamp, France References Farrer LA, Myers RH, Connor L, Cupples LA, Growdon JH (1991) Segregation analysis reveals evidence of a major
