Expanding Newborn Screening: Process, Policy, and Priorities

by VIRGINIA A. MOYER, NED CALONGE, STEVEN M. TEUTSCH, AND JEFFREY R. BOTKIN, ON BEHALF OF THE PREVENTIVE SERVICES TASK FORCE

In the 1960s, newborn screening programs tested for a single very rare but serious disorder. In

recent years, thanks to the development of new screening technology, they have expanded into panels of tests; a federally sponsored expert group has recommended that states test for twenty-nine core disorders and twenty-five secondary disorders. By the standards used to decide whether to introduce new preventive health services into clinical use, the decision-making in newborn screening policy has been lax.

hen a new medical technology is imple- hereditary and congenital conditions. The paradigm mented in a program that is supported by condition for newborn screening is , Wpublic funds and mandatory for all chil- a genetic metabolic disorder that causes permanent dren, the evidence that the technology is effective mental retardation unless who have it are should be solid. Unfortunately, in the last few years, identified before it is clinically apparent and placed newborn screening policy has not fully followed this on a special diet. State-mandated screening for PKU principle. More recently, efforts have been made to began in the 1960s and 1970s. Since then, states adhere more closely to an evidence-based approach have added a range of other conditions to their to newborn screening. In this article we review what screening panels depending on efficacy, program has been done in the past in order to inform the support, and local advocacy. Because of the paucity process going forward. of scientific information about efficacy, policy about All U.S. states and territories sponsor public which tests to make mandatory has historically var- health programs to screen newborns for selected ied considerably from state to state. In 2000, a national task force sponsored by the American Academy of and the federal Virginia A. Moyer, Ned Calonge, Steven M. Teutsch, and Jeffrey R. Health Resources and Services Administration called Botkin, on behalf of the United States Preventive Services Task Force, “Expanding Newborn Screening: Process, Policy, and Priori- for a standard list of conditions to be developed for ties,” Hastings Center Report 38, no. 3 (2008): 32-39. the state panels.1 HRSA then funded the American

32 HASTINGS CENTER REPORT May-June 2008 College of to con- term treatment and management. analysis screens for many con- vene a group of newborn screening The test is typically designed to mini- ditions at once.3 Tandem mass spec- experts who could fashion recom- mize the number of false negatives— trometry can replace the tests former- mendations for the list.2 In a report that is, results that incorrectly indi- ly used to screen for PKU while si- released in 2005, the ACMG group cate a child does not have a condi- multaneously screening for many called for all states to adopt a core tion—but usually the design involves other metabolic abnormalities—some panel consisting of twenty-nine pri- a tradeoff: changing test cutoff levels clinically significant and treatable, mary disorders for which evidence of to reduce the number of false nega- some clinically significant but not benefit was regarded as compelling, as tives increases the number of false treatable at this time, and others of well as twenty-five secondary disor- positives. unknown significance. ders that would be detected inciden- tally while screening for the core dis- orders. The report has been endorsed by an assortment of organizations, in- The methodology used to evaluate whether cluding advocacy groups, professional to include a condition on a panel placed associations, and the Advisory Com- mittee on Heritable Disorders and considerable weight on the multiplex Genetic Diseases in Newborns and Children, an official advisory body to capability of , the Secretary of the Department of Health and Human Services. giving preference to conditions it detects. In this paper, we express serious reservations about the rapid expan- sion of newborn screening programs A newborn screening program is The availability of tandem mass that is currently taking place without not just a panel of screening tests, spectrometry has led to considerable full consideration of all the issues at however. Ideally, it is also parental ed- pressure to expand newborn screen- stake. Screening recommendations ucation, follow-up, diagnosis, treat- ing. Parents of children who have for programs should be ment and management, and program candidate disorders, health profes- transparent, unbiased, evidence- evaluation, and all of the various parts sionals who treat these disorders, and based, and attentive to important so- of the system must be in place and private firms that sell screening tests cial values, especially if they will affect working well to realize the benefits of and equipment have all advocated for every child born in the United States. screening. the expansion of state programs. The original ACMG process did not Nonetheless, the test itself is what Campaigns inspired by the deaths conform to contemporary standards gets the most attention, and the tech- of children with undiagnosed medi- of evidence-based decision-making. nology available for the test has been um chain acyl-coenzyme A dehydro- In our view, state and federal policy- a critical factor driving the growth of genase deficiency (MCADD), a dis- makers should further evaluate each newborn screening. The invention of order of fatty acid metabolism, have condition proposed for screening be- the original PKU test and the card been particularly influential. People fore recommending that it be includ- used to store and transport the blood with MCADD cannot go without ed in a mandated screening panel. sample to the laboratory made public food for very long; fasting may cause newborn screening programs possi- them to suddenly experience hypo- The Technological Imperative ble. What has enabled the sudden ex- glycemia, vomiting, lethargy, seizures, pansion of newborn screening is the encephalopathy, coma, apnea, respira- xcept for a test for hearing im- availability of a new technology for tory arrest, cardiac arrest, and sudden Epairment, all of the tests in the conducting the tests. In the past, death.4 Management includes avoid- ACMG’s uniform panel are blood adding a new condition to a program ing fasting and taking nutritional sup- analyses. The newborn’s heel is stuck, meant adding new laboratory equip- plements. MCADD can be detected blood is collected on an absorbent ment to an already complex system. through tandem mass spectrometry, card, the card is sent to a lab, and the Now, however, most of the new con- and plainly the benefits for some chil- screening tests are carried out. Babies ditions recommended by the ACMG dren will be considerable. Advocates who test positive for a condition are group are detected using a single have argued very effectively for invest- referred for follow-up testing to con- method—tandem mass spectrometry ing in tandem mass spectrometry to firm the diagnosis, since false posi- (also known as MS/MS), which pro- identify children with MCADD, and tives are always possible. If the diag- duces results with a high degree of once the technology is in place, they nosis is confirmed, the child must precision and accuracy and permits argue that the state might as well test then be linked to appropriate long- multiplex testing, in which a single for the whole range of conditions that

May-June 2008 HASTINGS CENTER REPORT 33 tandem mass spectrometry can de- 4) How do the potential benefits consequences of untreated PKU were tect. compare with the possible harms so dire and the treatment so straight- The ACMG’s recommendations or costs of the intervention? forward and effective. Currently, were influenced by this perspective. newborns are screened for PKU with- The methodology that the ACMG 5) What constitutes “good out parental in all used to evaluate whether to include a enough” evidence for a policy deci- but a few states. (Some states give par- condition on a panel placed consider- sion? ents the right to refuse PKU screen- able weight on the multiplex capabil- ing, although parents frequently do ity of tandem mass spectrometry, giv- 6) What other considerations are not understand that they have that ing preference to conditions de- relevant to policy decisions? right.) tectable by the technology and mak- While not everyone accepts the ur- ing it more likely that they would be The framework is helpful for think- gency argument for foregoing in- selected for the uniform panel. ing about the ACMG group’s process, formed consent, even for PKU, others However, many of these disorders its uniform panel recommendations, have argued for less stringent ratio- are poorly understood or not treatable and the current newborn screening nales for newborn screening. For ex- (or both), and screening for such dis- expansion. ample, they assert that mandatory orders on a population basis departs screening can also be justified if, by from standard public health practice. The Ultimate Goal identifying infants with rare condi- Moreover, a newborn screening panel tions, it facilitates the research neces- should be expanded only if the new- he intervention at issue is sary to develop effective treatments. born screening program is fully pre- Tmandatory screening of all new- We find this rationale to be ethi- pared to make all the components of borns for certain rare hereditary and cally questionable. Mandating screen- the complex system available for the congenital disorders, with follow-up ing in order to recruit human research new disorders. Expansion would be to confirm diagnosis and initiate subjects does not conform to standard costly and might not be the best use treatment or management of the con- ethical or privacy requirements. Fur- of scarce health care resources, given dition. Justifying this intervention re- ther, research on rare metabolic con- the many other unmet child health quires that we make a special case for ditions cannot generate useful infor- needs. We present the rationale for its mandatory nature. Medical screen- mation without a research infrastruc- this perspective in the following sec- ing of children for a health condition ture that supports collaborative clini- tions. normally requires parental informed cal trials. Such an infrastructure exists consent, especially when the condi- for childhood cancer, but not yet for A Conceptual Framework for tion is not a threat to others in the rare metabolic conditions. Analysis of NBS Expansion community. Some argue that screening to iden- Several different rationales have tify potential subjects may benefit the ecently, in an important paper in been suggested for newborn screen- infants.6 In pediatric cancer care, for RHealth Affairs, David Atkins and ing, and whether screening can justifi- example, access to clinical trials en- colleagues suggested a framework that ably be mandatory may be considered hances the overall quality of care, es- policy-makers could use to sort independently for each. The most im- pecially for those children with poor through a controversy about whether portant and widely accepted goal of prognoses. However, there is no man- to adopt a new technology.5 The newborn screening is to improve dated testing of asymptomatic chil- Atkins framework asks six major health outcomes in the screened pop- dren for cancer in order to find chil- questions: ulation of newborns. Given this goal, dren to enroll in clinical trials of can- screening makes sense only if early de- cer treatment. We think that, at the 1) What is the ultimate goal, and tection and treatment will lead to bet- very least, informed decision-making how does the intervention achieve ter health outcomes than would be by the parents should be required those ends? possible if treatment were delayed prior to screening if the primary goal until the condition became sympto- is to identify potential subjects for re- 2) How good is the evidence that matic. search. the intervention can improve im- Meeting this condition requires Another goal sometimes suggested portant outcomes? that there be both a suitable test and a for newborn screening is the provi- treatment that is effective and works sion of information to parents about a 3) How good is the evidence that better if delivered before symptoms child’s health status. Advocates point the intervention will work in the appear. When PKU screening was in- to several reasons that providing in- setting specific to the policy- troduced, for example, proponents ar- formation is an appropriate screening maker? gued that mandatory, universal goal even when a condition has no screening was necessary because the proven medical treatment:

34 HASTINGS CENTER REPORT May-June 2008 • When the child develops symp- tion for reproductive decisions is the health status. If mandated public toms, the family can avoid the so- goal of screening, then parents should health screening of newborns is justi- called diagnostic odyssey—the give their informed consent to the fied on other grounds, then the infor- protracted search for an explana- screening. mation it produces might reasonably tion of a health problem. Similarly, while some parent advo- be an additional benefit, at least for cates speak eloquently about their de- some parents, as long as the harms are • The parents can avoid the impact sire to know about a child’s condition also taken into account. We believe, of a second affected child on the at birth so they can prepare them- however, that the goals of identifying family by incorporating informa- selves to provide appropriate care, potential research subjects and pro- tion about an inherited condition others may prefer to remain ignorant viding parents with information into their future reproductive deci- until symptoms appear if the child about a child’s future health status do sions.7 will realize no benefit from treatment not in themselves justify mandated administered before then. Given the screening of all newborns. Detecting • If the parents know something wide range in clinical presentations disorders that have no proven treat- about a child’s future health prob- lems, they can make plans for managing the impact of the condi- Several different rationales have been tion on the child and the family. suggested for mandatory newborn screening. • Knowing the information is valu- able in itself. Some assert that it can also be justified if, by

We find these points insufficient identifying infants with rare conditions, to justify mandated public health screening of all newborns. First, a di- screening facilitates research on treatments. agnostic odyssey does not begin until a condition becomes clinically mani- fest. If treatment need not begin until and the consequent uncertainty about ment or for which treatment is help- after symptoms appear, then why how an individual child will be affect- ful only after clinical presentation is mandate screening in newborns? Test- ed, the latter preference is quite rea- just not as urgent as detecting PKU.9 ing individuals might be more effec- sonable, and obtaining parental in- tive when symptoms first appear, formed consent would respect it. Evidence of Effectiveness since it would lead to fewer false pos- Finally, some have argued that itives. Clinical strategies to improve families have a “right to know” about n order to assess whether newborn diagnosis should also be considered. genetic diseases in their children even Iscreening can improve health out- Better clinical strategies would reduce if no effective treatment is available.8 comes as expected, policy-makers the probability of diagnostic odysseys In particular, some argue that if tan- need a great deal of information and are important even if newborns dem mass spectrometry is used at all, about the conditions, the associated are screened. Since screening always it should be used to test for all the ab- screening tests, and the entire new- produces some false negatives, physi- normalities it is capable of detecting, born screening program structure. cians must be able to recognize the and the information should be pro- For each condition, they need infor- clinical presentation of a condition re- vided to parents. This goal seems far mation on incidence and natural his- gardless of whether it is included in a removed from the goal of improving tory. How many infants will be iden- mandatory screening panel. health outcomes, however, and it vio- tified as having the condition, and of On the second point, opinions will lates a time-honored tenet of medi- those identified, how many will go on differ. Some parents may welcome in- cine that clinicians should not order a to develop noticeable symptoms? formation about the risk of an inher- test if the results will not change clin- Even when the natural history of clin- ited disorder in a future pregnancy, ical management. Moreover, provid- ically detected cases of a condition is but others may not. In this country, ing the information may have bad known, the natural history for screen- there is a strong ethical presumption consequences for the children and detected cases is often poorly under- that adults should decide what genet- their families—anxiety, changes in stood. Many children with screen-de- ic information they wish to have family relationships and dynamics, tected conditions may never develop about themselves, and there is an even unnecessary treatment, and labeling clinically important morbidity and stronger presumption that they that could lead to uninsurability. mortality, or they may be likelier to should make their own reproductive Certainly some parents will want have milder cases than those who are decisions. If the provision of informa- to obtain information about a child’s detected clinically.

May-June 2008 HASTINGS CENTER REPORT 35 Policy-makers also need informa- highly effective in reducing morbidity the grounds for the ACMG group’s tion on the availability of effective and mortality from the disease. Sever- recommendations were eventually treatments and whether early detec- al studies have found, however, that outlined in a lengthy report, and tion provides enough advantages to fewer than half of affected children HRSA announced a sixty-day public warrant screening. To justify manda- receive the recommended prophylac- comment period, but the report was tory public health screening of all tic measures, such as antibiotics and released for review and comment newborns, proven effective therapies immunizations.11 months after the recommendations or preventive strategies for included How good is the evidence of im- had become public knowledge and diseases should be available, and they provement and effectiveness for the had been endorsed and promoted by should be more effective when pro- disorders on the panel that the advocacy groups. vided before symptoms appear. Infor- ACMG group has recommended? It’s The detailed report describes a mation on the risks of treatment is hard to say. The push for expanded flawed process. In determining the also important. Unproven and poten- newborn screening has bypassed tra- recommended panel of tests, the tially harmful treatments are particu- ditional, evidence-based decision- ACMG report relied on an opinion larly bad for children who would not making processes at both the state survey chiefly of disease experts, screening specialists, and lay and pro- fessional advocates for screening, sup- The incidence and natural history of most plemented by unsystematic reviews conducted by selected disease experts. abnormalities identified through tandem The ACMG group developed its own criteria and weighting system to pri- mass spectrometry is uncertain, which means oritize disorders for inclusion. The there is uncertainty about the consequences system appeared to give as much or more weight to the testing technology of treatment. as to the health benefits of early de- tection, with a strong preference for the capability of detecting multiple have progressed to clinically impor- and federal levels. The ACMG disorders. Supplemental information tant disease in the first place. group’s task was to review the evi- about the estimated prevalence of Policy-makers also need informa- dence on the various conditions and these disorders demonstrated the lack tion on the characteristics of the decide which should be included in of robust epidemiological data. Very screening tests, such as rates of false the uniform panel. However, it devel- little attention was given to concerns positives and false negatives. When oped its own process—one that was about the quality of the evidence, the the entire newborn population is test- neither transparent nor open to inde- costs of expansion, or potential harms ed, even low rates of false positives pendent review. No experts in sys- from false positive screening results or with a very accurate test will lead to tematic reviews or evidence-based potentially unnecessary treatments. further testing for many babies. recommendation development were The report describes the twenty- Whether a large number of false pos- invited to participate or comment. nine disorders on the recommended itives is acceptable depends on the ex- The United States Preventive Services core panel as meeting three “mini- tent to which morbidity and mortali- Task Force, the Evidence-Based Prac- mum” criteria: each condition is iden- ty are prevented or ameliorated by tice Centers sponsored by the Agency tifiable twenty-four to forty-eight screening. for Healthcare Research and Quality, hours after birth; a high-throughput Finally, in order to ensure effec- the Centers for Disease Control’s Task screening test with “appropriate sensi- tiveness in local settings, policy-mak- Force on Community Preventive Ser- tivity and specificity” is available; and ers must have information about a vices, and the Institute of Medicine there are “demonstrated benefits of state’s ability to put all the pieces in were given no role in the process. early detection, timely intervention, place and create a system that works Other than specific newborn screen- and efficacious treatment.” The first for each disorder over the entire range ing specialists, state policy-makers criterion is straightforward. The sec- of circumstances prevailing through- were not involved, even though most ond is obscure, since “appropriate” is out the state. Even when a screening states have newborn screening adviso- not explained. Moreover, for many of intervention is shown to be effica- ry committees to advise the executive the conditions, there has been little or cious under controlled or experimen- and legislative branches of state gov- no recorded experience with large- tal circumstances, in actual practice it ernment, and two states (Massachu- scale population screening. Thus, may be substantially less.10 For exam- setts and Washington) conduct struc- what it means to meet this criterion is ple, early detection and prophylactic tured reviews of evidence pertaining hard to say. treatment for are to screening tests. The process and

36 HASTINGS CENTER REPORT May-June 2008 The third criterion is the most im- dence, context-free scientific evi- The report identifies significant barri- portant, but based on the informa- dence, and contextual scientific evi- ers to the construction of a model tion provided in the report, the un- dence.15 Colloquial evidence includes newborn screening system, including equivocal statement that all twenty- evidence about resources, expert inadequate state financing, fragment- nine core disorders satisfy it is also opinion, political judgment, values, ed service delivery, limited availability difficult to assess. For the group of habits, traditions, special interests, of metabolic disorder specialists, and metabolic abnormalities identified and other elements of the specific the absence of universal health cover- through tandem mass spectrometry issue. Context-free scientific evidence age. Both the ACMG report and the testing, some conditions are good consists of truths that are valid in any American Academy of Pediatrics’ candidates for early detection and context; this is what evidence-based 2000 newborn screening task force screening, given the evidence avail- medicine depends on most heavily. report indicate that many states have able. For example, good cases can be Contextual scientific evidence con- been struggling to overcome these made for early identification and sists of truths that are dependent on barriers for the conditions already in management of PKU and MCADD. the characteristics of the setting in their panels; if so, adding new condi- There is substantial experience with which the intervention takes place. tions will be difficult. In our judg- population-based screening and treat- All of the conditions on the ment, the ACMG group’s assessment ment of PKU and fairly good infor- ACMG core list can be supported by provides reason for concern about the mation about the prevalence of colloquial evidence, but only a small extent to which its uniform panel can MCADD, as well as some informa- number are well supported by either be effectively implemented on a na- tion about its natural history. Also, in- type of scientific evidence. The opin- tional basis. tervention appears to reduce the risk ion survey of disease experts and oth- of fatal metabolic crisis and has few ers was (at best) colloquial evidence. Benefits and Harms anticipated harms (although the latter In the second stage of the process, the have not yet been well character- evidence base was assessed and a fact n addition to the potential risks of ized).12 sheet was prepared for each disorder. Itreatment, all screening tests have For most other abnormalities iden- At least two recognized experts on more general potential harms: they tified through tandem mass spec- each disorder validated the fact sheets. may generate unnecessary worry, lead trometry, logic and a close reading of In the process, they ranked the avail- children to be labeled as having seri- the report reveal much greater uncer- able evidence about the condition, ous health problems, and have long- tainty about the incidence of these the test, the diagnosis, and the treat- term consequences for insurability abnormalities and their natural histo- ment on a scale of one to four, with and employability. If there were at ry in individuals identified through one being the gold standard: level one least fair evidence that an interven- screening. Given this fact, there is in- evidence is derived from well-de- tion was effective, the benefits could evitably less direct evidence of benefit signed randomized controlled trials or be large enough and certain enough and more uncertainty about the diagnostic studies on relevant popula- to allow a rough judgment that they health consequences of treatment. tions.16 (The rankings for each disor- outweighed the potential harms. Left unscreened, some children might der are shown in Appendix 1 of the However, when neither benefits nor never have known about their condi- report.) For many conditions, at least harms are well characterized, a more tions because they might never have one of the two experts categorized the cautious approach is warranted.19 If developed symptoms. Also, studies of available evidence as level three or the risk-benefit evaluation is inade- some conditions identify variants that four.17 In short, to argue that screen- quate, the program could end up do not affect the patient’s health, and ing will be good for children’s health, doing more harm than good. It might this variation argues against routinely the ACMG group (and other advo- also simply provide no demonstrable screening for such conditions.13 Even cates of screening) have at times given health benefit to the children while with MCADD, population screening up on good scientific evidence and re- spending scarce resources. Given tight studies suggest there are less severe ge- lied on extrapolation and supposition. state budgets for newborn screening netic variants for which the impact of (And, as noted, they have also argued programs and other essential child early detection and treatment is un- that screening can be justified by care services, resource consumption certain.14 goals other than direct health benefit without benefit must itself be consid- In a document titled, “Conceptu- to the child.18) ered a potential harm. alizing and Combining Evidence for In addition to assessing the evi- Health System Guidance,” the Cana- dence related to specific disorders, the Sufficiency of Evidence dian Health Services Research Foun- ACMG group assessed the ability of dation identifies three types of evi- states to carry out the activities re- he fifth question in the Atkins’ dence that evidence-based decision- quired to make screening for the uni- Tframework for deciding whether making may draw on: colloquial evi- form panel effective in local settings. to adopt a new technology is, What

May-June 2008 HASTINGS CENTER REPORT 37 constitutes “good enough” evidence for people in the newborn screening field collective resources, both public and a policy decision? The ACMG report is also a matter for concern. Current private, support public newborn appears to set the bar low. U.S. practice suggests that whether screening programs, decision-makers The United States Preventive Ser- evidence is thought to be sufficient to must also consider the preferences of vices Task Force (on whose behalf we introduce a new screening test de- the entire community concerning the write) also faces this question. The pends heavily on who evaluates it; ad- use of those resources, not just the USPSTF makes decisions about vocates of screening would likely preferences of those directly con- whether to introduce preventive ser- reach different conclusions than an cerned with newborn screening. Fi- vices, including screening tests, into independent decision-making body nally, they should ensure that their routine clinical care. The recommen- that incorporated health policy ex- decisions respect societal ethics relat- dations of the USPSTF are based on perts. In many states, colloquial evi- ing to the nature of benefit and harm comprehensive, systematic evidence dence provided by advocates and and to the significance of consent to reviews and assessments. Recommen- medical experts has been the domi- treatment and research. dations are made only when there is nant influence. Two states that con- It seems clear that the ACMG’s ap- evidence of at least fair quality that ducted structured reviews of scientific proach, which relied mostly on collo- the preventive service will result in evidence, Massachusetts and Wash- quial evidence, failed to adequately real net benefit. In the absence of ington, have implemented tandem demonstrate effectiveness. It also good or fair quality evidence, the mass spectrometry programs that failed to incorporate the views of the USPSTF issues an “I Statement”: mandate screening for far fewer con- community at large on the proper there is insufficient evidence to rec- ditions than are called for by the place of newborn screening within ommend for or against. ACMG core panel.20 Massachusetts the allocation of health care resources Based on the ACMG fact sheets mandates screening for MCADD but to child health needs. and the validation reports characteriz- makes other testing optional. Wash- ing the evidence, we believe that if the ington currently includes MCADD Recommendations ACMG list of core conditions were in its screening panel and is in the evaluated using the USPSTF ap- process of reconsidering other disor- high standard of evidence should proach, a few would be recommend- ders in the ACMG core panel. Abe met before requiring that all ed with an A or B grade, meaning infants be screened for a disorder. We that there is at least fair evidence that Other Relevant Considerations believe that at least some of the twen- the benefits outweigh the harms. Per- ty-nine conditions ACMG has identi- haps a few more would receive C he paradigm of evidence-based fied as “core conditions” for screening grades; the evidence is at least fair, but Tmedicine has recently shifted do not meet conventional population what the evidence shows is that bene- somewhat to include nonscientific in- screening criteria, including the mini- fits and harms are too closely bal- formation, such as the values of the mal criteria proposed by the ACMG anced to support an across-the-board individual being tested or treated. At report. We do not know how many of recommendation about introducing the policy level, for example, Neal these conditions would meet objec- the service. The majority, however, Kohatsu has defined evidence-based tive criteria for population screening would be given an I: there is insuffi- public health as the integration of sci- because the process by which this list cient evidence to recommend for or ence-based interventions with com- was produced excluded the evidence- against. Without performing full- munity preferences.21 Similarly, the based approaches accepted by the re- scale evidence reviews of our own, of Canadian Health Services Research search community in evaluating med- course, we cannot be sure; but if we Foundation states that the three types ical and public health interventions. are right, the ACMG recommenda- of evidence it identifies—colloquial Perhaps the rarity of candidate condi- tion that these conditions be adopted evidence, context-free scientific evi- tions for screening and the desire to by all state newborn screening pro- dence, and context-sensitive scientific support a politically popular program grams is premature. Good public evidence—require a deliberative derailed the process. health practice and good ethics re- process including consultation with State policy-makers should ask quire that the evidence threshold be relevant stakeholders in order to reach some probing questions before fol- at least as high for a recommendation an evidence-based judgment. lowing the ACMG recommenda- for mandatory screening of all new- The same is true of the decisions tions. Parents should be able to borns through a public health pro- regarding newborn screening: those choose whether their children will un- gram as it is for recommendation of a ultimately responsible for setting dergo screening when the evidence on nonmandatory test for use in clinical health policy at the national, state, or benefits and harms is equivocal or care with informed consent. even health care system level must limited. If policy is to move in that di- The fact that the ACMG’s expert balance the scientific and other evi- rection, however, more attention group was composed primarily of dence supporting screening. Since must be given to ways of involving

38 HASTINGS CENTER REPORT May-June 2008 parents as active participants in new- to make evidence-based recommen- Mortality Weekly Report 49, no. 32 (2000): born screening programs, and re- dations. This is an important step for- 729-31. search is needed on prenatal educa- ward in newborn screening policy 12. S.D. Grosse and C. Dezateux, “New- born Screening for Inherited Metabolic tion and prenatal permission for un- that should not only inform recom- Disease,” Lancet 369 (2007): 5-6. proven newborn screening. mendations about new tests, but also 13. B.T. van Maldegem et al., “Clinical, We suggest that both state and be used to review and update recom- Biochemical, and Genetic Heterogeneity in federal governments should objective- mendations about tests on the cur- Short-Chain Acyl-Coenzyme A Dehydroge- ly evaluate each condition on the rent core list. We strongly support nase Deficiency,” Journal of the American basis of prevention potential, medical this initiative and encourage full Medical Association 296 (2006): 943-95. rationale, treatment availability, pub- funding so that the process can pro- 14. B. Wilcken et al., “Screening New- borns for Inborn Errors of Metabolism by lic health rationale, available technol- ceed without delay. Tandem Mass Spectrometry,” Journal of the ogy, and cost-effectiveness before rec- American Medical Association 348 (2003): ommending inclusion in mandated References 2304-2312. 15. J. Lomas et al., for the Canadian screening panels. Stakeholders, in- 1. American Academy of Pediatrics, Health Services Research Foundation, cluding content experts and advocacy Newborn Screening Task Force, “Serving “Conceptualizing and Combining Evidence organizations, should participate in the Family from Birth to the Medical for Health Systems Guidance,” 2005, Home: Newborn Screening a Blueprint for this process, but not to the exclusion http://www.chsrf.ca/other_documents/evi- the Future,” Pediatrics 106, no. 2, supple- of evidence-based policy experts who dence_e.php. ment (2000): 389-427. are experienced in the objective evalu- 16. The evidence levels used in the Amer- 2. American College of Medical Genetics ican College of Medical Genetics report ation of scientific evidence. Because Newborn Screening Expert Group, “New- were determined as follows: Level one evi- the scientific evidence is rapidly born Screening: Toward a Uniform Screen- dence was derived from well-designed ran- evolving, we recommend that states ing Panel and System: Executive Summary domized controlled trials or diagnostic stud- and Main Report,” Genetics in Medicine 9, revisit their lists on a regular basis— ies on relevant populations. Level two evi- no. 5, supplement (2006): 1S-252S. perhaps every three to five years. dence was derived from well-designed ran- Finally, we urge that if states ex- 3. D. Marsden, C. Larson, and H.L. domized controlled trials or diagnostic stud- Levy, “Newborn Screening for Metabolic ies with minor limitations and/or over- pand newborn screening to include Disorders,” Journal of Pediatrics 148 (2006): disorders for which the evidence of whelming, consistent evidence from obser- 577-84. vational studies. Level three evidence was benefits and harms is incomplete, 4. Centers for Disease Control, National derived solely from observational studies. then they should commit to collect- Office of , Level four evidence was derived from expert ing longitudinal data on infants who “MCAD Deficiency Medium-chain acyl- opinion, case reports, and reasoning from test positive. Although the data will CoA dehydrogenase,” fact sheet; basic principles. http://www.cdc.gov/genomics/hugenet/fact 17. For twelve of the twenty-nine core be strongly biased (because all or sheets/FS_.htm, accessed September 11, nearly all children identified by conditions, the experts’ rankings of the evi- 2007. dence levels differed by more than one cate- screening are likely to be treated, re- 5. D. Atkins, J. Siegel, and J. Slutsky, gory; for example, one expert might consid- gardless of whether the treatment will “Making Policy When the Evidence Is in er the evidence for the benefit of treatment alter health outcomes), this informa- Dispute,” Health Affairs 24, no. 1 (2005): to be level one, and another might consider tion should help us learn from our ex- 102-113. it level three. This is surprising, since the de- periences and implement truly effec- 6. D. Alexander and P.C. van Dyck, “A finitions of the levels are clear. One would Vision of the Future of Newborn Screen- expect more agreement from experts review- tive, evidence-based screening pro- ing,” Pediatrics 117, no. 5 (2006): S350-54. ing a single body of literature. grams. Given the imminent arrival of 7. Ibid. 18. R.R. Howell, “We Need Expanded yet newer and more powerful screen- 8. Ibid. Newborn Screening,” Pediatrics 117, no. 5 (2006): 1800-1805. ing technologies, we should put a 9. S.D. Grosse et al., “From Public high priority on getting the processes Health Emergency to Public Health Service: 19. J.R. Botkin et al., “Newborn Screen- in place to assure sound, evidence- The Implications of Evolving Criteria for ing Technology: Proceed With Caution,” based decisions. Newborn Screening Panels,” Pediatrics 117 Pediatrics 117, no. 5 (2006): 1793-99. The Advisory Committee on Her- (2006): 923-29. 20. K. Atkinson et al., “A Public Health Response to Emerging Technology: Expan- itable Disorders and Genetic Diseases 10. J.R. Botkin, “Research for Newborn Screening: Developing a National Frame- sion of the Massachusetts Newborn Screen- of Newborns and Children has work,” Pediatrics 116, no. 4 (2005): 862- ing Program,” Public Health Reports 116 moved forward on many of the issues 71. (2001): 122-31; S.D. Grosse and M. Gwinn, “Assisting States in Assessing New- recommended in this paper. They 11. S.J. Teach, K.A. Lillis, and M. Grossi, born Screening Options,” Public Health Re- have committed to directing a sys- “Compliance with Penicillin Prophylaxis in ports 116 (2001): 169-72. tematic evidence review for all new Patients with Sickle Cell Disease,” Archives 21. N.D. Kohatsu et al., “Evidence-Based conditions nominated by experts and of Pediatric and Adolescent Medicine 152 (1998): 274-78; “Update: Newborn Screen- Public Health: An Evolving Concept,” advocates for consideration as addi- ing for Sickle Cell Disease: California, Illi- American Journal of Preventive Medicine 27, tions to the current testing recom- nois, and New York, 1998,” Morbidity and no. 5 (2004): 417-21. mendations, and to use these reviews

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