[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.163.92.62. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Article
January 2003

Minimizing RisksThe Ethics of Predictive Diabetes Mellitus Screening Research in Newborns

Author Affiliations

From the Department of Pediatrics and MacLean Center for Clinical Medical Ethics, The University of Chicago, Chicago, Ill.

Arch Pediatr Adolesc Med. 2003;157(1):89-95. doi:10.1001/archpedi.157.1.89
Abstract

Type 1 diabetes mellitus is the most common metabolic disease of childhood. Two states offer newborn screening to identify children with a genetic predisposition to it. It is a voluntary test offered in conjunction with the mandatory newborn metabolic screening. There are no preventive treatments, but children discovered to be at increased risk may participate in follow-up studies to determine whether and when the child develops autoantibodies (preclinical disease) or overt diabetes. This study examined the ethics of predictive genetic research in newborns for type 1 diabetes. Prediction research has serious psychosocial implications, and research designs must account for them. The study concluded that, to minimize harm to infants and their families, (1) if the research does not incorporate a prevention strategy, studies should avoid disclosure of results; and (2) if disclosure is necessary, then the research should be restricted to newborns with an affected first-degree relative.

In the United States, type 1 diabetes mellitus has an annual incidence of 15 per 100 000 younger than 18 years, making it the most common metabolic disease of childhood.1 Of major concern is that type 1 diabetes is increasing at a yearly rate of 2.5%.2 In January 2002, a Florida newspaper proclaimed that "Florida had taken a progressive step in becoming the first state offering to screen newborns for the risk of developing juvenile diabetes."3(p8A) The newborn screening involves identifying children with a genetic predisposition to type 1 diabetes. It will be offered as a voluntary test in conjunction with the mandatory newborn metabolic screening. Infants discovered to be at increased risk will be recruited for follow-up studies to determine whether and when the child develops autoantibodies (preclinical disease) or overt diabetes. This article examines the ethics of predictive diabetes screening research in newborns.

DIABETES PREDICTION STUDIES IN NEWBORNS

Florida's interest in diabetes prediction research in newborns is not unique. The BABY-DIAB studies in Germany and Australia are prospective studies from birth of children who have at least 1 parent with diabetes mellitus. The studies are designed to perform serial blood tests on the children for evidence of autoantibody development48 and its relationship with environmental triggers.6,8

Although newborns with an affected first-degree relative have a 10-fold higher incidence of developing type 1 diabetes,9 most newborn studies do not focus on these children because they account for only 10% of type 1 diabetes cases.10,11 The Diabetes Prediction and Prevention (DIPP) study in Finland seeks to identify all newborns with HLA-DQB1 genotypes that confer a high (˜8%) or moderate (1.7%-2.6%) risk of developing type 1 diabetes (compared with a national average risk of 0.7%).12 Approximately 94.4% of parents consent togenetic screening, and 14.8% of the children are found to be at increased risk.12 The Norwegian Babies Against Diabetes (NOBADIA) study seeks to identify the 4% of newborns in the general population with the highest genetic risk (12%) of developing insulin-dependent diabetes mellitus.13 Begun in 1998, this study will follow up these infants for 15 years. In Colorado, the Diabetes Autoimmunity Study in the Young (DAISY) seeks to identify newborns with the highest genetic risk alleles (˜2.3%) to participate in serial antibody screening10; 94% of mothers consent.10 The Florida newspaper report3 refers to the Prospective Assessment in Newborns for Diabetic Autoimmunity (PANDA) study in which infants at increased genetic risk will be observed for antibody development to uncover possible environmental triggers such as breastfeeding, immunizations, and viral infections.14

To date, the only combined prediction-prevention study in newborns is a prevention trial in Finland (the Trial to Reduce IDDM in the Genetically at Risk [TRIGR]). After encouraging results of a pilot study in 1992 to 1993,1 the second TRIGR pilot study was launched in 1995 to examine whether avoiding cow's milk protein for the first 6 to 8 months of life prevents diabetes in infants with an affected first-degree relative.15 The diet was effective in non-obese diabetic mice,16 although some preliminary data suggest that it is ineffective in humans.17,18 After weaning from breast milk, infants enrolled in TRIGR receive exclusively either a casein-hydrolysate formula that lacks intact cow's milk (Nutramigen; Mead Johnson & Co, Evansville, Ind) or another formula (Enfamil [Mead Johnson & Co], with 20% Nutramigen to control for taste and smell).15 No results are available yet.

All of the studies described above include disclosure of the child's genetic risk to the parents. Contrast such disclosure with the consensus in the medical and medical ethics communities against clinical predictive genetic testing of children when no treatment exists.1922 Yet, despite the medical and ethical consensus against clinical predictive testing, more than 90% of parents consent to research predictive screening of their newborns for diabetes. In the next 3 sections, I address the following questions: (1) What are the risks and benefits of such newborn research screening? (2) What is required for newborn research screening to be ethical? (3) Do current newborn research screening projects fulfill these ethical requirements?

THE RISKS AND BENEFITS OF DIABETES SUSCEPTIBILITY RESEARCH IN NEWBORNS

The expert consensus against isolated predictive identification of newborns and children for increased genetic susceptibilities when no preventive measures are available is based on the lack of therapeutic benefit.1925 When psychosocial risks and benefits of predictive identification are mentioned, it is presumed that the risks outweigh the benefits.19,21,23

However, there are scant empiric data regarding the psychosocial risks and benefits of predictive screening with disclosure of results of children generally,26,27 let alone for newborn screening for a specific condition like type 1 diabetes. Although the NOBADIA study plans to do extensive psychological follow-up,13 there are very few data on the psychosocial risks associated with identifying newborns for a genetic predisposition to diabetes.28 The data that do exist regarding predictive diabetes identification are from studies in families who were notified that children (beyond infancy) or adults had islet cell antibodies (a marker of β-cell destruction).2933 These studies found that families were initially quite anxious, but most of the anxiety dissipated by 4 months.2933 However, anxiety persisted in some subgroups (eg, those who relied on self-blame and wishful thinking as coping strategies3133), such that the researchers concluded that some participants may experience greater distress than others.32,33

In addition, whether the anxiety will remain low needs to be determined. Psychological follow-up from other newborn screening programs suggest that harms can accrue over a much longer period, and that they can wax and wane. Consider, for example, α1-antitrypsin deficiency screening begun in Sweden in the early 1970s.34,35 α1-Antitrypsin deficiency is an autosomal recessive predisposition to chronic lung disease in young adulthood with variable penetrance and expressivity. Parents of at-risk children were counseled that smoking and smoky environments could hasten or worsen their children's pulmonary symptoms. Psychological data were procured for 20 years on a subset of families with a child who screened positive.3441 The data showed that parents initially had strong negative emotional reactions to the diagnosis,34 and yet, most parents had positive feelings that the screening program identified their child's risk.37

The α1-antitrypsin deficiency screening program was stopped after 5 years because of the psychological stress it had caused in some families whose child had tested positive.38 Follow-up data found increased smoking by fathers of affected children34 and negative long-term effects in the mental and physical health of the mother39,41,42; in mother-child but not father-child interactions41; in parents' long-term emotional adjustment to their children's α1-antitrypsin status40; and in the parents' view of their children's health,40 although this improved over time.36 However, the children, as young adults, were aware of the dangers of smoking and smoky environments and were positive about α1-antitrypsin deficiency screening.43 In 1997, the World Health Organization reviewed the data and published a memorandum in support of implementing newborn screening for α1-antitrypsin deficiency.44 Although Sweden remains somewhat ambivalent,45 Oregon had a similar program in the 1970s46 and supports reimplementation.47

α1-Antitrypsin deficiency and type 1 diabetes are not completely analogous. First, as noted by the α1-antitrypsin deficiency researchers, some of the psychological stress might have been avoided if the parents had been informed about the testing and given the opportunity to consent to or refuse testing, which was not the case when α1-antitrypsin deficiency testing was incorporated into universal screening programs in the 1970s.45 All of the predictive diabetes newborn screening programs described above include a separate informed consent process. Yet, even if a special informed consent is required, it may not be enough, in part because "the pressure of the hospital setting, the parents' physical and emotional condition immediately after birth, and the cultural belief that ‘medical testing is good for you' will lead most parents to consent."48(p107) A second dissimilarity between the 2 conditions is that there are preventive measures that can be taken for α1-antitrypsin deficiency that improve the benefit-harm ratio for α1-antitrypsin deficiency screening. One would hypothesize greater harm in predictive information about type 1 diabetes when subjects and their families have no control over the development of diabetes.49,50

What, then, are the risks and benefits of predictive identification of newborns at increased risk for type 1 diabetes? One potential clinical benefit is that parents can be taught the signs and symptoms of clinical disease so that their children are diagnosed early, and avoid being diagnosed in the emergency setting of diabetic ketoacidosis. The risk, however, is that parents may overreact and interpret a child's normal urination habits as a sign of polyuria. A second potential clinical benefit is that the parents will be familiar with a diabetes center and will make the transition to clinical care more easily. However, a high-risk allele does not confer certainty of disease, and parents may become very anxious and make life plans based on an increased susceptibility, a susceptibility that has less than a 20% probability of fruition; and a low-risk allele may give parents false reassurance of their child's health because some children with low-risk genetic alleles develop diabetes.

The most serious clinical risk, however, is that parents will conflate the experimental and nontherapeutic nature of diabetes screening with the therapeutic newborn screening programs geared to detect metabolic and endocrine disorders that require immediate treatment. Parents may decide that all newborn screening is experimental and refuse phenylketonuria and diabetes screening, despite the high medical benefit of the former. Alternately, parents may conflate the experimental and therapeutic screening and consent to both without understanding that the former is nontherapeutic. This will leave them unprepared for a positive test result. Data show that the receipt of a positive test result has more negative effects than anticipated in population-based screening (vs fewer negative effects than anticipated in testing of high-risk families).51

There are also potential psychosocial benefits and risks to newborn diabetes screening programs. One potential psychosocial benefit is that the parent can prepare. Yet, given the high rate of false-positive results (the highest-risk allele confers less than a 20% risk of developing diabetes), many parents will prepare unnecessarily, and the danger is that they may begin treating their child as being ill, when the child has at most an increased risk of becoming ill in the future.40 This is particularly true when the genetic factor is but one contributor to a higher relative risk of an illness that also depends on unknown individual or environmental cofactors.52 It may also adversely affect the parent-child relationship.41,53,54 This risk may be exaggerated in the newborn period, which is a particularly vulnerable time in parent-child relationships.54,55 Even families who have received a positive screening test that is quickly confirmed to be negative (eg, false-positive hypothyroid screen) report greater strain on marriage and difficulties in their relationships with their children.56 Imagine, then, a positive screening test that reflects only increased susceptibility over a lifetime! These children may spend their childhood as neither healthy nor ill but "at risk."57,58 Such labeling may cause familial stress36,53,54 and may be stigmatizing for the family, as reflected in difficulty procuring health insurance.52,54,59

The concerns about genetic discrimination in health insurance are serious. Several studies have documented that genetic information leads to discrimination in health insurance.60,61 The institutional review board guidebook prepared by the Office for Human Research Protections specifically states that subjects in genetic research must be made aware of the potential for discrimination in health and life insurance.62

If the benefits do not clearly outweigh the risks, why do 94% of parents consent to screening for type 1 diabetes? In part, the high uptake can be explained by our culture's unequivocal support of testing generally.48,63 The low frequency of positive results in the general population makes it attractive to individuals who seek reassurance.64,65 The high uptake may also be explainable, in part, because of how the test is offered. Data show that uptake is highest when requested in person and when testing can be done immediately.65 In the case of newborn screening for type 1 diabetes, the blood may already have been procured (DAISY) or will be procured for traditional newborn screening.

MINIMIZING RISKS TO CHILDREN

Although the diabetes community clearly supports diabetes research in the general population of newborns,3,66 the question remains whether current study designs minimize risk, a requirement enumerated by various reports on what is required for research to be ethical in general,6770 as well as in reports focusing on research with children.71,72 In the United States, this requirement was adopted into the federal regulations regarding the protection of human research subjects (§46.111).73 Several reports also note that, because of the vulnerability of children, research should be conducted when possible on animals, then adults, and then older children.69,71,72 Unfortunately, the demographics of type 1 diabetes1,2,74 and the increasing number of new cases of children younger than 4 years74,75 mean that such research must be done on young children.

One question is whether it matters if the research is done on newborns or older infants. Newborns are attractive for population genetic screening research because (1) virtually all newborns in developed countries are born in hospitals (captive population); (2) virtually all undergo screening for phenylketonuria and hypothyroidism, making screening already accepted; and (3) large amounts of blood can be obtained from the placenta at delivery without any physical risk to the infant. A delay of 3 months would not interfere with predictive research, as autoantibodies and overt disease rarely develop before then.12 The advantage of such a delay is that it would distinguish this research study from current metabolic newborn screening. The major drawback of such a study design would be lower participation. Attempting to enroll children at primary care clinics is much less efficient than enrollment in the hospital. It requires the active recruitment by many primary care physicians who may not have a vested interest in the project and may not be willing to spend the time to get consent from the parent. It would also require a separate blood sample, which both increases the physical riskiness of the study (albeit minimally) and could result in a lower rate of parental consent.

Whether such a precaution is necessary would depend on whether the increased vulnerability of newborns and the newborn-parent relationship53,54 is significantly reduced by 3 months. However, even if this is not the case, one could argue, at minimum, in support of decision aids to improve the consent process76 or a more active parental consent process. Consider, for example, the suggestion by Clarke,77 one of the principal investigators of a voluntary newborn screening program for Duchenne muscular dystrophy, a progressive neuromuscular disorder for which no treatment exists. Duchenne muscular dystrophy screening has been offered in Wales for the last decade, and it also has a 94% uptake rate.77 Clarke suggested that requiring more active parental involvement (eg, requiring parents to mail the blood spot for the Duchenne muscular dystrophy screening) may lead to a lower, "more appropriate" uptake rate: "To suggest that a lower uptake rate for a screening test would be preferable, that we should set a threshold of motivation so that infants are not screened unless their parents actively choose it, is certainly unusual but is perfectly appropriate in the context of an untreatable disease."77(p115)

Again, the analogy is not perfect. Duchenne muscular dystrophy is uniformly fatal, whereas type 1 diabetes is treatable, although currently there does not exist a treatment for either condition that can be provided presymptomically that will prevent or delay the onset of the disease.78,79 Duchenne muscular dystrophy is also virtually 100% penetrant (the likelihood of developing the disease if one has the gene), in contrast to the genetic markers for type 1 diabetes that result only in an increased susceptibility. This means that many newborns identified as being at increased risk for type 1 diabetes will not develop the disease. There are many dangers in creating awareness and labeling individuals "at risk" in a low-risk population77,80: leading to vulnerable child syndrome, inappropriately treating the child as being "ill" even before symptoms develop, or trying unproven and potentially dangerous preventive measures.30,57,58,8082 Thus, because the genetic markers for type 1 diabetes offer only predispositional information and no preventive measures are available, one could make an argument, similar to Clarke's, that infants should not be screened unless the parents actively choose it; 94% uptake seems too high.

Another way to reduce risk in genetic susceptibility research is to design studies that do not require disclosure of individual results because nondisclosure eliminates the psychosocial harms of classifying an individual as "at risk." In such a study, one would request parental permission (1) to procure a blood sample of the infant and (2) to track whether the infant develops diabetes by annual contact with local hospitals, pediatric endocrinologists, diabetes registries, or the families themselves. In Sweden, long-term studies have been done in this way.83

Critics might object to this study design requirement for 3 reasons. First, they may object on the grounds that parents will not consent to genetic testing of their newborns under these conditions, but that is an empiric question for which there are no data. Second, critics might also object because a policy of nondisclosure in the general population means that follow-up autoantibody screening studies will be more expensive because the researchers cannot target those at high risk. This concern is valid and will require innovative study designs. At minimum, consent should be sought not only for procuring the blood sample but also for permission to obtain follow-up data from third parties. Third, critics may object that my solution is overly paternalistic. They will point to the fact that 94% of parents consent to research participation. I have already tried to explore why the uptake is higher than it would be if parents truly understood the risks and benefits of such research before they consented. But even if only 20% of informed parents consented, the critics' cry of paternalism must be addressed.

Paternalism is "the intentional overriding of one person's known preferences or actions by another person, where the person who overrides justifies the action by the goal of benefiting or avoiding harm to the person whose will is overridden."84(p274) However, the situation at hand is not about interfering with an individual's decision about whether to participate in research, but whether to interfere in a parent's autonomy about whether to enroll his or her child in research. The issue, then, is about whether to respect not individual autonomy but parental autonomy. Proxy decision making is more restricted than individual autonomy because individuals may take risks that they cannot authorize others to take.85,86 As such, it is morally justifiable to require that risk status not be disclosed to minimize the research risks for individuals who cannot consent for themselves.

If one wants to focus one's research on the development of autoantibodies in individuals with increased genetic susceptibility, these individuals need to be identified for periodic retesting, or one would need to rescreen entire sample populations periodically. The latter becomes cumbersome and expensive, given that one is often interested in a small percentage of the population. For example, in DAISY, the researchers identified 2.3% of the population as high risk (meaning that the individual infant has a 1 in 15 chance of developing type 1 diabetes by the age of 20 years)87 vs a 1 in 250 chance in the general population.88

If one assumes that the research has scientific merit, and that it is unrealistic to assume that it can be done without identifying individuals "at risk," the question remains who is the appropriate subject population. Given the demographics of the disease, it will require the participation of young children. However, there is also the question of whether such research should be done on the general population, or only in newborns from high-risk families (ie, a family with an affected first-degree relative). The scientific advantage of screening the low-yield general population is that it will increase the number of infants identified. The advantage of selectively screening the high-risk community is that one will identify a larger number of individuals "at risk" with a smaller sample. The major disadvantages of recruiting only from high-risk families are that the total number identified may be too small for some research and fear that this sample population may be biased. For example, most studies have concluded that islet cell antibodies are less predictive in the general population than in high-risk families,8991 with the exception of Schatz et al92 in the United States.

The answer becomes clearer if one uses the criteria that research must be designed to minimize risks, including psychosocial risks. There is some empiric evidence to support restricting the identification of risk to children in high-risk families. Children in these families are often viewed as "at risk" even before genetic markers were discovered and are often labeled as such by their families even if they do not undergo genetic testing.93,94 The parents' behavior is not without merit: Siblings have a 15-fold increased chance of developing type 1 diabetes compared with an individual from the general population. In addition, although the data are anecdotal, parents in families in which either a parent or child has diabetes frequently do monitor their other children for signs of glycosuria or hyperglycemia.9496 The exact percentage is unknown because this fact is rarely shared with physicians.95 Given the baseline anxiety that already exists within these families, genetic and immunologic testing does not induce the anxiety4,25,95 but rather either confirms or refutes these concerns, albeit only probabilistically.

A policy that distinguishes newborns in high-risk families from newborns in the general population may also be more consistent with current regulations regarding children as research subjects.97 The federal regulations permit minimal-risk research to be done on all children, but they restrict research that entails a minor increase over minimal risk to subjects who have the disease or condition being studied.97 If "disease or condition" is understood to include children at risk for the particular disease or condition, then one could justify restricting more than minimal risk research to children from high-risk families because these children are at risk as a result of the genetic basis of diabetes. I argue for this interpretation elsewhere (L.F.R., unpublished data, 2002).

Finally, one must consider prediction research that is coupled with prevention. Clearly, the children need to be identified for the prevention strategy to be used. Both the concern of introducing the "at-risk" status into the healthy population and the high false-positive rate have led many ethicists to conclude that initial studies should be restricted to children from high-risk families, despite their therapeutic potential.24,25,98

DO CURRENT RESEARCH DESIGNS MINIMIZE RISK?

Population studies are important to understand incidence, prevalence, and gene-environment interactions of type 1 diabetes in the general population. However, the identification of at-risk newborns in the general population and the disclosure of these results to unsuspecting parents fail to minimize risks, an ethical requirement for all research involving human subjects. Population studies that are designed to disclose the results to parents in order to follow up subjects prospectively need to be redesigned. This includes many of the studies being done today, including DIPP, NOBADIA, DAISY, and PANDA.

Even if one focuses on infants from high-risk families, the ethical requirement to minimize risk would support designing predictive studies that do not require disclosure of the results. Virtually all of the German and Australian BABY-DIAB data could have been procured without disclosing results (except for 13 children from whom the German researchers requested more frequent testing because they had more than one positive antibody6; while this additional information may have been valuable, it greatly increased the potential psychosocial harms of the research and could have been omitted).

If it is necessary to disclose the risk status of infants, then the study population ought to be restricted to infants from families with an affected first-degree relative. For example, if the research includes a prevention strategy, identification of at-risk children will be necessary. Given the potential harms of introducing at-risk status into the healthy population, initial studies should recruit only children from high-risk families, as TRIGR did.

CONCLUSIONS

Type 1 diabetes is a significant health problem in children, and accurate prediction in infancy will be necessary to prevent or delay its onset. However, prediction research in the newborn period has potentially serious psychosocial implications, particularly when it is being introduced into the unsuspecting general population, and research designs must account for them. To minimize harm to infants and their families, I propose 2 recommendations. First, if the research is solely predictive (ie, it does not incorporate a prevention strategy), studies should be designed, when possible, to avoid disclosure of increased susceptibility results. Second, if disclosure is necessary, then the research should be restricted to children with an affected first-degree relative, and this would hold even for prediction-prevention protocols.

Article
Back to top
Article Information

Corresponding author: Lainie Friedman Ross, MD, PhD, Department of Pediatrics, The University of Chicago, 5841 S Maryland Ave, MC 6082, Chicago, IL 60637 (e-mail: lross@uchicago.edu).

Dr Ross's research on genetics is supported by a Harris Foundation (Chicago) grant, "Ethical and Policy Implications of Genetic Testing of Children." Dr Ross's research on children in research is funded by grant NLM 1 G13 LM07472-01 from the National Institutes of Health, Bethesda, Md. Dr Ross is also a member of the Internal Organizational Advisory Group for the Policy and Ethics Section of the Collaborative Network for Clinical Research on Immune Tolerance, also known as Immune Tolerance Network, sponsored by the National Institutes of Health. The opinions expressed in this article represent her own views, and do not necessarily reflect the views of the National Institutes of Health, the Immune Tolerance Network, or the Harris Foundation.

Accepted for publication September 18, 2002.

What This Study Adds

Although there is wide consensus against predictive genetic screening in children for adult-onset conditions when no treatments can be implemented in childhood, there is virtually no discussion about the ethics of predictive genetic screening in infants and children for conditions that present in childhood when no treatments can be implemented before symptoms appear. There is also scant discussion on how to perform predictive screening research in children ethically. This article argues that such research must conform to the ethical principle that research should be designed to minimize risk to children and their families. It then considers whether current research fulfills this criterion.

References
1.
Not Available, Prevention of Type 1 Diabetes Mellitus (Conference Summary from American Diabetes Association). Available at: Diabetes Forumhttp://www.diabetesforum.net/cgi-bin/display_engine.pl?category_id = 15&content_id = 230Accessed June 18, 2002
2.
Heine  RJ Diabetes in the next century: challenges and opportunities. Neth J Med. 1999;55265- 270Article
3.
Not Available, Infant diabetes test is good start [editorial]. St Petersburg Times. January8 2002;8A
4.
Ziegler  A-GHummel  MSchenker  MBonifacio  E Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes. 1999;48460- 468Article
5.
Hummel  MFuchtenbusch  MSchenker  MZiegler  A-G No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care. 2000;23969- 974Article
6.
Roll  UChristie  MRFuchtenbusch  MPayton  MAHawkes  CJZiegler  A-G Perinatal autoimmunity in offspring of diabetic parents: the German Multicenter BABY-DIAB Study: detection of humoral immune responses to islet antigens in early childhood. Diabetes. 1996;45967- 973Article
7.
Colman  PGSteele  CCouper  JJ  et al.  Islet autoimmunity in infants with a type 1 diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia. 2000;43203- 209Article
8.
Couper  JJ Annotation: environmental triggers of type 1 diabetes. J Paediatr Child Health. 2001;37218- 220Article
9.
Buzzetti  RQuattrocchi  CCNistico  L Dissecting the genetics of type 1 diabetes: relevance for familial clustering and differences in incidence. Diabetes Metab Rev. 1998;14111- 128Article
10.
Flanders  GGraves  PRewers  M Review: prevention of type 1 diabetes from laboratory to public health. Autoimmunity. 1999;29235- 246Article
11.
Dahlquist  GG Primary and secondary prevention strategies of pre-type 1 diabetes: potentials and pitfalls. Diabetes Care. 1999;22Suppl 2B4- B6
12.
Kimpimaki  TKupila  AHamalainen  A-M  et al.  The first signs of B-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type I Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab. 2001;864782- 4786
13.
Ronningen  KS Genetics in the prediction of insulin-dependent diabetes mellitus: from theory to practice. Ann Med. 1997;29387- 392Article
14.
Greener  M PANDA identifies babies at risk of developing type 1 diabetes. Mol Med Today. 2000;63Article
15.
Paronen  JKnip  MSavilahti  E  et al.  Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Diabetes. 2000;491657- 1665Article
16.
Karges  WHammond-McKibben  DCheung  RK  et al.  Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk–based IDDM Prevent Trial. Diabetes. 1997;46557- 564Article
17.
Norris  JMBeaty  BKlingensmith  G  et al.  Lack of association between early exposure to cow's milk protein and β-cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY). JAMA. 1996;276609- 614Article
18.
Couper  JJSteele  CBeresford  SD  et al.  Lack of association between duration of breast feeding or introduction of cow's milk and development of islet autoimmunity. Diabetes. 1999;482145- 2149Article
19.
Institute of Medicine, Assessing Genetic Risks: Implications for Health and Social Policy.  Washington, DC National Academy Press1994;
20.
Working Party of the Clinical Genetics Society (UK), The genetic testing of children. J Med Genet. 1994;31785- 797Article
21.
American Society of Human Genetics/American College of Medical Genetics, Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 1995;571233- 1241
22.
American Academy of Pediatrics, Committee on Bioethics, Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;1071451- 1455Article
23.
Kodish  E Testing children for cancer genes: the rule of earliest onset. J Pediatr. 1999;135390- 395Article
24.
Siegler  MAmiel  SLantos  J Scientific and ethical consequences of disease prediction. Diabetologia. 1992;35(Suppl. 2)S60- S68Article
25.
Nordenfelt  L Prevention and ethics in medicine: the case of diabetes prevention. J Pediatr Endocrinol Metab. 1996;9381- 386Article
26.
Michie  SMarteau  TedRichards  Med Predictive genetic testing in children: paternalism or empiricism. The Troubled Helix: Social and Psychological Implications of the New Genetics. Cambridge, England Cambridge University Press1996;177- 183
27.
Broadstock  MMichie  SMarteau  TM The psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet. 2000;8731- 738Article
28.
Yu  MSNorris  JMMitchell  CM  et al.  Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants. Am J Med Genet. 1999;86219- 226Article
29.
Johnson  SBRiley  WJHansen  CANurick  MA Psychological impact of islet cell-antibody screening: preliminary results. Diabetes Care. 1990;1393- 97Article
30.
Johnson  SBTercyak  KP Psychological impact of islet cell-antibody screening for IDDM on children, adults and their family members. Diabetes Care. 1995;181370- 1372Article
31.
Carmichael  SLJohnson  SBWeiss  AFuller  KGShe  JXSchatz  DA Psychological impact of screening programs in mothers of children at-risk for type 1 diabetes [abstract]. Diabetes. 2000;49(suppl 1)A317
32.
Johnson  SB Screening programs to identify children at risk for diabetes mellitus: psychological impact on children and parents. J Pediatr Endocrinol Metab. 2001;14653- 659Article
33.
Weber  BRoth  R Psychological aspects in diabetes prevention trials. Ann Med. 1997;29461- 467Article
34.
Thelin  TMcNeil  TFAspegren-Jansson  ESveger  T Psychological consequences of neonatal screening for α1-antitrypsin deficiency: parental reactions to the first news of their infants' deficiency. Acta Paediatr Scand. 1985;74787- 793Article
35.
Heyerdahl  S Psychological problems in relation to neonatal screening programmes. Acta Paediatr Scand. 1988;77239- 241Article
36.
Thelin  TMcNeil  TFAspegren-Jansson  ESveger  T Identifying children at high somatic risk: parents' long-term emotional adjustment to their children's α1-antitrypsin deficiency. Acta Psychiatr Scand. 1985;72323- 330Article
37.
Thelin  TMcNeil  TFAspegren-Jansson  ESveger  T Psychological consequences of neonatal screening for α1-antitrypsin deficiency: parental attitudes toward "ATD-check-ups" and parental recommendations regarding future screening. Acta Paediatr Scand. 1985;74841- 847Article
38.
McNeil  TFThelin  TAspegren-Jansson  ESveger  THarty  B Psychological factors in cost-benefit analysis of somatic prevention: a study of the psychological effects of neonatal screening for α1-antitrypsin deficiency. Acta Paediatr Scand. 1985;74427- 432Article
39.
Thelin  TMcNeil  TFAspegren-Jansson  ESveger  T Identifying children at high somatic risk: possible long-term effects on the parents' view of their own health and current life situation. Acta Psychiatr Scand. 1985;71644- 653Article
40.
McNeil  TFThelin  TAspegren-Jansson  ESveger  T Identifying children at high somatic risk: possible effects on the parents' views of the child's health and parents' relationship to the pediatric health services. Acta Psychiatr Scand. 1985;72491- 497Article
41.
McNeil  TFHarty  BThelin  TAspegren-Jansson  ESveger  T Identifying children at high somatic risk: long-term effects on mother-child interaction. Acta Psychiatr Scand. 1986;74555- 562Article
42.
Sveger  TThelin  TMcNeil  TF Neonatal α1-antitrypsin screening: parents' views and reactions 20 years after the identification of the deficiency state. Acta Paediatr. 1999;88315- 318Article
43.
Sveger  TThelin  TMcNeil  TF Young adults with α1-antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition. Acta Paediatr. 1997;8637- 40Article
44.
Not Available, α1-Antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75397- 415
45.
Sveger  TThelin  T A future for neonatal α1-antitrypsin screening? Acta Paediatr. 2000;89628- 631Article
46.
O'Brien  MLBuist  NRMMurphey  WH Neonatal screening for alpha1-antitrypsin deficiency. J Pediatr. 1978;921006- 1010Article
47.
Wall  MMoe  EEisenberg  JPowers  MBuist  NBuist  AS Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr. 1990;116248- 251Article
48.
Wertz  DBurley  JedHarris  Jed Testing children and adolescents. A Companion to Genetics. Oxford, England Blackwell Publishers2002;92- 113
49.
Senior  VMarteau  TMPeters  TJ Will genetic testing for predisposition for disease result in fatalism? a qualitative study of parents responses to neonatal screening for familial hypercholesterolaemia. Soc Sci Med. 1999;481857- 1860Article
50.
Lefcourt  HM Locus of Control: Current Trends in Theory and Research. 2nd ed. New York, NY Halstead1982;
51.
Michie  SMarteau  TMClarke  AJ, eded Predictive genetic testing in children: the need for psychological research. The Genetic Testing of Children. Oxford, England Bios Scientific Publishers1998;169- 181
52.
Croyle  RTLerman  CCroyle  RT, eded Psychological impact of genetic testing. Psychosocial Effects of Screening for Disease Prevention and Detection New York, NY Oxford University Press1995;11- 38
53.
Headings  VE Counselling in a hospital-based newborn screening service. Patient Counsel Health Ed. 1980;280- 83Article
54.
Clayton  EW What should be the role of public health in newborn screening and prenatal diagnosis? Am J Prev Med. 1999;16111- 115Article
55.
Fyro  K Neonatal screening: life-stress scores in families given a false-positive result. Acta Paediatr Scand. 1988;77232- 238Article
56.
Tymstra  T False positive results in screening test: experience of parents of children screened for congenital hypothyroidism. Fam Pract. 1986;392- 96Article
57.
Davison  CMacintyre  SSmith  GD The potential social impact of predictive genetic testing for susceptibility to common chronic disease: a review and proposed research agenda. Sociol Health Illn. 1994;16340- 371Article
58.
Meadow  CK The last well person. N Engl J Med. 1994;330440- 441Article
59.
Reilly  PRBoshar  MFHoltzman  SH Ethical issues in genetic research: disclosure and informed consent. Nat Genet. 1997;1516- 20Article
60.
Billings  PRKohn  MAde Cuevas  MBeckwith  JAlper  JSNatowicz  MR Discrimination as a consequence of genetic testing. Am J Hum Genet. 1992;50476- 482
61.
Geller  LNAlper  JSBillings  PRBarash  CIBeckwith  JNatowicz  MR Individual, family, and societal dimensions of genetic discrimination: a case study analysis. Sci Eng Ethics 1996;271- 88Article
62.
Office for Human Research Protections, Institutional Review Board Guidebook, chap 5, part H: Human Genetic Research. Available at http://ohrp.osophs.dhhs.gov/irb/irb_chapter5ii.htm#h12Accessed October 16, 2002
63.
Nelkin  DTancredi  L Dangerous Diagnostics: The Social Power of Biological Information.  New York, NY Basic Books1989;
64.
Andrykowski  MALightner  RStudts  JLMunn  RK Hereditary cancer risk notification and testing: how interested is the general population? J Clin Oncol. 1997;152139- 2148
65.
Marteau  TMCroyle  RT The new genetics: psychological responses to genetic testing. BMJ. 1998;316693- 696Article
66.
Schatz  DAKrischer  JPSyler  JS Therapeutic controversy: now is the time to prevent type 1 diabetes. J Clin Endocrinol Metab. 2000;85495- 498Article
67.
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research.  Washington, DC National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research1979;
68.
Not Available,Reich  WT, eded Nuremberg Code, 1946, Principle 1. Encyclopedia of Bioethics New York, NY Free Press1978;41764
69.
World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. Adopted by the 18th World Medical Association (WMA) General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996; and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000.Available at:http://www.faseb.org/arvo/helsinki.htmAccessed October 16, 2002
70.
Medical Research Council of Canada, Natural Science and Engineering Research Council of Canada, Social Science and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.  August1998;Available athttp://www.nserc.ca/programs/ethics/english/ethics-e.pdfAccessed June 18, 2002
71.
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Report and Recommendations: Research Involving Children.  Washington, DC National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research1977;
72.
Nicholson  RHed Medical Research With Children: Ethics, Law and Practice.  The Report of an Institute of Medical Ethics Working Group on the Ethics of Clinical Research Investigations on Children. Oxford, England Oxford University Press1986;
73.
Department of Health and Human Services (45 CFR 46 Subpart A), Final regulations amending basic HHS policy for the protection of human research subjects. 46Federal Register 8366 (1981), revised 56 Federal Register 280031991;
74.
EURODIAB ACE Study Group, Variation and trends in incidence of childhood diabetes in Europe. Lancet. 2000;355873- 876Article
75.
Feltbower  RGMcKinney  PABodansky  HJ Rising incidence of childhood diabetes is seen at all ages and in urban and rural settings in Yorkshire, United Kingdom. Diabetologia. 2000;43682- 684
76.
Entwistle  V The potential contribution of decision aids to screening programmes. Health Expectations. 2001;4109- 115Article
77.
Clarke  AJHarper  PSedClarke  AJed Newborn screening. Genetics, Society and Clinical Practice. Oxford, England Bios Scientific Publishers1997;107- 117
78.
Escolar  DMScacheri  CG Pharmacologic and genetic therapy for childhood muscular dystrophies. Curr Neurol Neurosci Rep. 2001;1168- 174Article
79.
Diabetes Prevention Trial–Type 1 Diabetes Study Group, Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002;3461685- 1691Article
80.
Davison  CMacintyre  SSmith  GD The potential social impact of predictive genetic testing for susceptibility to common chronic disease: a review and proposed research agenda. Sociol Health Illn. 1994;16340- 371Article
81.
Burris  SGostin  LOBurley  JedHarris  Jed Genetic screening from a public health perspective: three "ethical" principles. A Companion to Genetics Oxford, England Blackwell Publishers2002;455- 464
82.
Clarke  AJHarper  PSedClarke  AJed The genetic dissection of multifactorial disease: the implications of susceptibility screening. Genetics, Society and Clinical Practice. Oxford, England Bios Scientific Publishers1997;93- 106
83.
Samuelsson  USundkvist  GBorg  HFernlund  PLudvigsson  J Islet autoantibodies in the prediction of diabetes in school children. Diabetes Res Clin Pract. 2001;5151- 57Article
84.
Beauchamp  TLChildress  JF Principles of Biomedical Ethics. 4th ed New York, NY Oxford University Press1994;274
85.
Buchanan  AEBrock  DW Deciding for Others: The Ethics of Surrogate Decision Making.  New York, NY Cambridge University Press1989;
86.
Ross  LF Children, Families, and Health Care Decision Making.  Oxford, England Oxford University Press1998;
87.
Rewers  MBugawan  TLNorris  JM  et al.  Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia. 1996;39807- 812Article
88.
Buzzetti  RQuattrocchi  CCNistico  L Dissecting the genetics of type 1 diabetes: relevance for familial clustering and differences in incidence. Diabetes Metab Rev. 1998;14111- 128Article
89.
Veijola  RReijonen  HVahasalo  P  et al.  HLA-DQB1–defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. J Clin Invest. 1996;982489- 2495Article
90.
Bingley  PJBonifacio  EShattock  M  et al.  Can islet cell antibodies predict IDDM in the general population? Diabetes Care. 1993;1645- 50Article
91.
Landin-Olsson  MPalmer  JPLernmark  A  et al.  Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. Diabetologia. 1992;351068- 1073Article
92.
Schatz  DKrischer  JHorne  G  et al.  Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. J Clin Invest. 1994;932403- 2407Article
93.
Marteau  TM Psychology and screening, narrowing the gap between efficacy and effectiveness. Br J Clin Psychol. 1994;331- 10Article
94.
Wagner  ATibben  ABruining  GJ  et al.  Preliminary experience with predictive testing for insulin-dependent diabetes mellitus. Lancet. 1995;346380- 381Article
95.
Lucidarme  NDonmingues-Muriel  ECastro  DCzernichow  PLevy-Marchal  C Appraisal and implications of predictive testing for insulin-dependent diabetes mellitus. Diabetes Metab. 1998;23550- 553
96.
Shepherd  MHattersley  ATSparkes  AC Predictive genetic testing in diabetes: a case study of multiple perspectives. Qual Health Res. 2000;10242- 259Article
97.
Department of Health and Human Services (45 CFR 46 Subpart D), Additional Protections for Children Involved as Subjects in Research. 48 Federal Register 9814-20 (1983); revised 56 Federal Register 28,032 (1991).
98.
Roth  R Psychological and ethical aspects of prevention trials. J Pediatr Endocrinol Metab. 2001;14669- 674Article
×