What newborn screening strategies are available for diagnosis, what is the effectiveness of these strategies, and what cost savings are generated by screening and treatment?
Description of Current Screening Process
There is general agreement that treatment of infants with PKU should be instituted within about three weeks of birth to prevent neurological damage from the disease. Reaching this goal requires competence of a number of complex, interrelated systems: specimen collection, specimen transport and tracking, laboratory analysis, data collection and analysis, contacting families of infants with abnormal results, diagnosis, treatment, long-term management and quality assurance (Simpson et al., 1997). Success also depends upon educating families, public health workers and primary care providers about the screening process, the disease itself and the required treatment. Difficulties in execution or communication in any of these areas can cause disruption of a successful screening program (Council of Regional Networks for Genetics Services [CORN], 1999).
Efficient, effective laboratory methods for mass screening of newborns has been a quest of scientists, practicing physicians and public health agencies for many years. Bickel et al. (1953) and Bickel et al. (1954) reported an effective dietary treatment for reducing the brain damage resulting from PKU. They suggested that early detection and a restricted phenylalanine diet could prevent mental retardation in individuals with PKU, a result shown by Armstrong and Tyler (1955). In the mid and late 1950's, the "wet diaper" test was performed in hospital nurseries and physicians' offices as a preliminary screening technique. This test relied on Fölling's observation that excessive phenylpyruvic acid in urine produced a green color change in the presence of ferric chloride (Koch and de la Cruz, 1999).
In the early 1960's, mass screening of newborn infants for PKU became possible, following Guthrie's development of a simple, effective laboratory procedure which tested specimens collected on filter paper (Guthrie, 1961). This methodology created a practical and accurate technique for screening newborn infants for PKU. Blood collected on filter paper is stable, easily transported, and causes minimal inconvenience to medical personnel, families, and infants.
All current screening methods are designed to detect an elevation of phenylalanine, not the deficiency of phenylalanine hydroxylase activity (Dougherty and Levy, 1999). The Guthrie Bacterial Inhibition Assay (BIA) is the method used by most mass screening programs in the United States (Dougherty and Levy, 1999). In the Guthrie BIA, a phenylalanine-free minimal agar base is seeded with Bacillis subtilis spores and an inhibitor, beta-thienylalanine, is added to suppress growth of the organism. The action of the inhibitor is blocked by the presence of phenylalanine, thereby allowing the B. subtilis to grow in the area surrounding the filter paper blood disk containing phenylalanine. The size and density of the growth zone is directly dependent upon the amount of phenylalanine present (Aldis et al., 1993).
The Guthrie test has been found to have high sensitivity, however, the test is semi-quantitative and difficult to automate. Its accuracy can be affected by factors such as the presence of antibiotics in the blood at the time of specimen collection (Dougherty and Levy , 1999). While Dougherty and Levy only rate the Guthrie as having "moderate" sensitivity, there is little information in recent literature speaking to false negative results using this method. Articles often reference Holtzman et al. (1986) which states that 1 out of 70 cases of PKU were missed by U.S. screening programs. The study timeframe was from the beginning of newborn screening programs in this country through 1983. There were 43 missed PKU cases in this study. Twenty-five of those cases were due to laboratory errors. However, 40% of the missed PKU cases occurred in private or hospital laboratories. Currently, PKU screening in this country is done in large regional, state or multi-state laboratories.
The other primary method currently used in mass screening programs is automated fluorometric analysis. This procedure yields a quantitative chemical analysis of phenylalanine eluted from dried blood spots collected on filter paper. The procedure has been used successfully for confirmation and quantitation of specimens initially analyzed by the Guthrie BIA procedure, and is used by some states for mass screening of newborns for PKU (Dougherty and Levy, 1999).
For fluorometry, false positive rates of 0.02% to 0.64% on the first screen are compared with 5% on the Guthrie assay, although second blood samples were required in 0.15% of cases for both methods. The test seems to be as reliable as the Guthrie BIA and may be slightly more sensitive (Jew et al, 1994).
Another potential screening method is high performance liquid chromatography (HPLC). HPLC offers the advantages of automation, high accuracy, and multiple determinations for hyperphenylalaninemias, maple syrup urine disease (MSUD), and homocystinuria in a single run (Dougherty and Levy, 1999). However, although HPLC yields precise and accurate concentrations for six amino acids, it gives no indication of how these measurements should be used to achieve maximal classification accuracy or minimal false positives. It also has been too slow for large-scale screening (Dougherty and Levy, 1999). HPLC is used in some instances for confirmation of abnormal screening results of Guthrie and other methods, but not as a primary screening method.
In the past two years, Food and Drug Administration (FDA) has approved commercial kits to detect phenylalanine hydroxylase deficiency from blood spots (Dougherty and Levy, 1999). These kits are either colorimetric or fluorometric, quantitative, and utilize microtiter plates. Thus laboratories working in microtiter plate configuration for other tests are likely to find these to be more convenient than Guthrie plates, and more quantitative than the Guthrie (Fingerhut et al., 1997).
Over the past decade, development and improvements in the application of tandem mass spectrometry (TMS) for newborn screening for phenylketonuria and other disorders has been underway. TMS has been demonstrated to significantly reduce the incidence of false positives when tyrosine levels are simultaneously measured TMS for newborn screening would allow states to detect a large number of amino acid, organic acid and fatty acid oxidation disorders. This technology allows for diagnosis of phenylketonuria, MSUD, homocystinuria and numerous other disorders of amino, organic and fatty acid metabolism in a single analytical run (Dougherty and Levy, 1999).
The technical complexity and the need for sophisticated interpretation of the results for other disorders suggest that this expansion be carried out cautiously. According to Levy (1998), expansion to TMS could require fundamental change in the newborn screening programs operating in this country, because "with few exceptions, health department screening programs do not have and are not likely to acquire and retain the expertise required to adequately perform tandem mass spectroscopy analysis and interpret the results in a timely manner." Similarly, Chace and Naylor (1999) conclude, "Newborn screening by [TMS] is on the verge of a very rapid expansion, but its technical complexity and the need for sophisticated interpretation of the results will dictate that this expansion be carried out cautiously and with intelligent planning by experienced laboratories." A recent survey of state public health labs indicates that 11 states are currently using TMS, and an additional 21 states are considering its use in the near future.
In terms of overall effectiveness of current PKU screening, there is little information available in the literature about false negative tests and affected children missed in other parts of the newborn screening system and, if affected children are being missed by current systems, liability concerns and legal settlement agreements may preclude fully accurate reporting. The U.S. Preventive Service Task Force Guide to Clinical Preventive Services (1996) concludes that "international experience with its use in millions of newborns suggest that false-negative results are rare."
For more than 21 years, the Centers for Disease Control and Prevention and the Association of Public Health Laboratories have conducted research on materials development and assisted laboratories with quality assurance for newborn screening. Their 1999 performance data on phenylketonuria qualitative assessments of 124 laboratories and 2480 assayed specimens found 1.4% transcription errors, 0.9% false positive misclassifications, and 0.3% false negative misclassifications. Overall 115 labs correctly identified specimens, 5 labs made transcription errors, and 9 labs misclassified specimens. Statistical analysis of quality control data demonstrated similar results for bacterial inhibition, HPLC, fluorometry and TMS. (Association of Public Health Laboratories and CORN, 1999)
Discharging hospital-born infants prior to 24 hours of age has also been cited as a potential problem (McCabe, et al., 1983; Dougherty and Levy, 1999). Most standards recommend 24 hours of protein feedings prior to taking the blood sample for newborn screening. Early discharge could lead to false negative results if levels of phenylalanine had not risen to cut-off levels. Various hospitals and state newborn screening programs have instituted policies to overcome these potential problems, including mandated second screens and/or home visits.
Variations in Screening Protocols
While all 50 states screen newborns for phenylketonuria, these programs vary in their approaches, procedures and policies concerning the storing, analysis and release of dried blood spot specimens after completion of the newborn screening processes. There is also a lack of uniformity between states, and between developed nations regarding the laboratory methods utilized to screen newborns for PKU.
There have been efforts to develop recommendations for standard practice in screening programs. For example, it is recommended that a newborn screening specimen be collected from all infants as close as possible to the time of discharge from the nursery, but no later than seven days of age. If the initial specimen is collected before 24 hours of age, a second specimen should be collected before two weeks of age. Testing is performed on a small amount of blood obtained on a filter paper collection device, air dried, and submitted to a newborn screening laboratory. Only two sources of filter paper have been approved by the FDA for blood collection in the United States. These papers must meet the national criteria for acceptable performance (Hannon et al., 1997). The screening system is designed to minimize false negative results, while avoiding overburdening the medical system with false positive results.
The variation in practice has a potential impact on the effectiveness of newborn screening strategies in that not all families receive the same level of care. The Committee on Genetics of the American Academy of Pediatrics published a policy statement on newborn screening in September of 1996 (American Academy of Pediatrics, 1996). Included in this policy statement is some basic background material on newborn screening as well as fact sheets providing detailed information on many of the conditions that are commonly tested for in various states. The fact sheets were developed to assist pediatricians in understanding the specific characteristics and the strengths and weaknesses of the testing methods. This policy statement acknowledges the following; "Newborn screening is an individual function of each state; therefore, screening programs are not uniform throughout the United States." A table is provided that details the variation in practice among states.
The 1996 report titled, "Newborn Screening, An Overview of Newborn Screening Programs in the United States, Canada, Puerto Rico and the Virgin Islands," provides specific details about multiple components of newborn screening programs (CORN, 1996). Great variations in practice are evident in all areas of testing including which conditions are included in the testing protocols. All but one state in the U.S. (Maryland) mandate screening, as do four provinces in Canada as well as Puerto Rico. Parental refusal is permitted in all but four U.S. states and one province in Canada. Some U.S. states have a newborn screening advisory board, some charge a fee and some rescreen samples while other states participate in these activities at varying levels. Some states offer various educational services and follow-up, while others do not offer such services. For states that charge a fee, some bill the patients while others bill the referring doctor, hospital or third party provider. Funding sources and services covered by these funding sources vary greatly. Methods for tracking and screening also vary among providers. All states in the U.S., all provinces in Canada as well as Puerto Rico and the Virgin Islands test for PKU.
A draft of the Executive Summary: Recommendations from the Newborn Screening Task Force titled, "Serving the Family from Birth to the Medical Home, Newborn Screening: A Blueprint for the Future", also addresses the great variation from state to state in practice in all components of the newborn screening process. The American Academy of Pediatrics convened this task force in response to a request from the Maternal and Child Health Bureau of the Health Resources and Services Administration, and the U.S. Department of Health and Human Services. Because of this variation in practice, the task force noted that not all newborns have access to the same level of care. Recommendations were made to improve the newborn screening program in the U.S. and include the development of minimum standards and guidelines and adequate funding to support programs (Lloyd-Puryear et al., 2000).
The debate over whether a newborn screening program should be voluntary or mandatory is long standing and as yet unresolved. This debate is tied to the issue of effectiveness of testing protocols. Along with this deliberation is the consideration of parental informed consent. Discussions surround the questions of whether parental informed consent should be required, is desirable but not really possible, is indicated in some circumstances but not others and so on. Informed consent is a major issue because American health care practices are grounded in the respect for patient autonomy. In addition, with the exception of child abuse or neglect, parents are considered to be in the best position to make medical decisions for their children. In the practice of medicine in America today, it is the rare case where patients and families do not have the right to participate in their health care decisions. Because of this, the determination to exclude parents in the decision process for newborn screening tests has been questioned (Fost, 1993; 1992; Paul, 1999).
Holtzman et al. (1983) completed a study to determine whether knowledge of the mother was improved as a result of obtaining informed consent as part of a newborn screening program. The results of the study showed that a consent process could improve mothers' knowledge about the cause and effect of the disorders tested for, the effectiveness of treatment, the type of testing done, and the interpretation of the results. In addition the authors state that, "Requiring parental consent for neonatal screening is cost beneficial; parental knowledge is increased without incurring significant time or effort costs, and with extremely few refusals." This study does not indicate that informed consent is necessary for all procedures. The study also attempted to distinguish between informing parents and obtaining consent when asking parents how they would like to be involved in such decisions. In this study, 80% of all mothers wanted to be informed and 50% of all mothers wanted the opportunity to consent (Holtzman et al., 1983).
On the other hand, Statham and colleagues wrote a letter to the British Medical Journal concerning mothers consenting to newborn screening (Statham et al. 1993). In Wales, hospitals perform newborn screening for Duchenne Muscular Dystrophy as well as other conditions, including PKU. Informed consent is a part of this newborn screening process. These researchers attempted to assess the knowledge base of the mothers about newborn screening after they left the hospital with their babies. They found that the knowledge base was low although the mothers believed themselves to be informed. They conclude that these results challenge the notion that women are giving informed consent.
In an earlier publication Faden et al. (1982), argue that informed consent specifically in the case of newborn screening for PKU, is not morally justified. Their reasoning is that, "a public policy that grants parents the right to consign their children to a state of irreversible mental retardation is not morally acceptable." They are concerned that offering this testing as an option assumes that parents have the right to refuse and that this right is questionable.
No major publication was identified as taking issue with the mandatory testing of newborns specifically for PKU. Although many publications discuss the numerous problems encountered with the early stages of the PKU screening programs where screening was instituted before anyone really knew much about the accuracy of the testing and the effectiveness of the treatment, PKU screening is mostly considered a success story. Since the early days of newborn screening, problems such as confidentiality and stigmatization have been discussed (Erbe, 1981; Fletcher, 1987).
The issue of informed consent appears to be of a major concern today because of the potential for expanding newborn screening testing options. The major concerns center around which new tests should be added to screening programs; whether any tests should be dropped from programs; who makes these decisions; what should be done with information gained that does not directly affect the health of the newborn, such as carrier testing results; whether parents should be required to submit to some testing but not all; and what follow-up services should be available for families. For instance, consideration has been made toward testing for additional conditions such as Cystic Fibrosis, Duchenne Muscular Dystrophy, and HIV (Edwards 1996; Gretchell et al., 1993; Bradley et al., 1993). These are conditions for which either there is no treatment or treatment may not be effective and therefore the question of whether or not all parents would want to know this information is of particular concern. In terms of PKU screening, these concerns are most germane in the context of TMS, through which additional diseases could be screened for, simultaneous with PKU.
In an editorial to the American Journal of Public Health in 1997, Holtzman addresses this issue of rapidly expanding genetic screening programs. The major concern addressed is the increasing ability to test for more conditions in the newborn period (Holtzman 1997). The issues include how decisions are made about what to test for, who makes those decisions, and whether it is appropriate for all tests to be mandatory. Holtzman argues for community involvement in such decisions. In analyzing informed consent, he points out that the state of Maryland repealed its mandatory newborn screening law and now requires parental informed consent. He reports that a systematic review of screening decisions throughout the state found that over 99.9% of parents offered newborn screening, for PKU and several other illnesses, consented to have it done on their newborn.
Hiller et al. (1997) also address the issue of public involvement in formulating and implementing policy in the newborn screening arena. They surveyed all state programs to assess all aspects of the newborn screening process. One argument they make is that studies have shown that involving consumers in decision-making results in better outcomes regarding the potential for improvement in follow up and patient compliance. Again, they address the issue of great variation in policy that exists among states. In their study, 49 out of 51 states (including the District of Columbia), report that educational materials are available to parents, but only 13 states require parental notification or the distribution of materials prior to testing and, although many states permit parental refusal, there are no legal or regulatory assurances that parents will be informed of this option.
In a 1994 publication of the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine , the Committee on Assessing Genetic Risks made recommendations for newborn screening programs, as well as other areas of genetic testing (Andrews et al., 1994). Concerning the issue of mandatory testing, the committee made the following recommendation: "The committee recommends that newborn screening programs be voluntary. The decision to make screening mandatory should require evidence that – without mandatory screening – newborns will not be screened for treatable illnesses in time to institute effective treatment (e.g., for PKU or congenital hypothyroidism)." In other words, this group affirmed what many others have concluded about newborn screening when examining this issue: mandatory screening specifically for PKU is justified but for many other tests, it would be appropriate to include the parents in the decision about whether or not to test.
Blood obtained from newborns for the purposes of screening tests is collected from a heel stick onto filter paper. In almost all cases, there is a sample of blood left over after the testing is completed. Most screening programs store these filter papers that hold the left-over blood spots obtained from all infants in the state. These blood spots are a source of genetic material for a multitude of research studies. There has been some discussion surrounding the questions of who should have access to these samples, under which circumstances, if any, these samples should be available, and whether the parents should have the right to refuse to have their child's genetic material used in a research study. The American Society of Human Genetics (1990) issued a "Points to Consider" document that addresses this and other issues surrounding DNA identification. In this document, the committee recommends that access to DNA samples should be permitted when the data are to be analyzed anonymously or with prior written permission. The Newborn Screening Task Force Report also addresses this issue. The Task Force recommends that permission from parents should be sought when the samples with identifying information from their infant will be used in research. Other related recommendations are made to ensure the ethical use of linked (unidentifiable) samples. These recommendations include the development of a consent process prior to the collection of samples that addresses the issue of the potential for future research (Lloyd-Puryear et al., 2000).
A related document that is useful is the consensus statement of joint effort between the NIH and CDC, published in 1995, addressing the issue of informed consent for genetic research on stored tissue samples (Clayton et al., 1995). The authors state that, "as is true for adults, research using linkable or identified tissue samples from children, particularly to search for mutations that cause specific disease, usually poses greater than minimal risk. As a result, permission must be sought from a parent of the source." Specific recommendations of this group include considerations for making identifiable samples anonymous for research. One recommendation was to consider whether the samples are finite and, if used for research, they would no longer be available for other uses. Other recommendations included considering whether it is possible to obtain consent, the soundness of the research, the possibility of recontacting participants, and appropriateness of pursuing anonymous research. In addressing the issue of future collection of samples, it was stated that, "people should have the opportunity to decide whether their samples will be used for research."
It is generally maintained that genetic counseling should be a component of newborn screening programs. The rationale given is that one of the many goals of a newborn screening program is to provide the family with counseling about the disorder, the associated risks for recurrence, and reproductive options. The described goals of genetic counseling not only include educating the family about the diagnosis and recurrence risks but also to provide supportive counseling to the family. In addition, some screening tests result in the identification of unaffected carriers. This information also has reproductive consequences for many family members (American Academy of Pediatrics, 1996; Scriver, 1963; Scriver and Clow, 1980; Wallman and Witt, 1998; and Committee on Genetics, 1992).
In addition, counseling services are considered an important component in the care of an adult woman affected with PKU due to the teratogenic nature of the condition (Levy and Ghavami, 1996).
Published recommendations generally state that genetic counseling should be a component of a newborn screening program, but strategies to fund this service get less attention. In general, families are made aware of genetic counseling services although some states fund a genetic counselor on staff and cover educational services (CORN, 1996).
There are different forms of economic analysis of health interventions, and the different forms of analyses put different emphases on the various economic and health impacts itemized above. The two dominant forms of analysis that currently in health economics are cost-benefit analysis (CBA) and cost-utility analysis (CUA, sometimes referred to as cost-effectiveness analysis, CEA). Of these, CUA has emerged as the more widespread approach.
The accepted methodologies for CBA and CUA in the evaluation of health interventions has evolved substantially over the past decade. There are now widely-agreed upon procedures for conducting CUA and CBA, guidelines for which have published in leading journals and widely accepted textbook-length methodological guidelines exist, e.g., Gold et al, 1996.
Seymore et al. (1997) identify ten published economic evaluations of PKU screening, most of which employ CBA. They are: Bush et al. (1973); MDPH (1974); Komrower et al. (1979), Alm et al. (1982), Holtzman (1983), Barden et al. (1984); Dagenais et al. (1985), Dhont et al (1991), Cockburn et al (1992), Hisachige (1994), and Sprinkle et al. (1994). Collectively they employ data from the USA, England, Sweden, Canada, France, Scotland, and Japan.
Seymore et al. (1997) find that, "Very different assumptions were made across the different studies about outcomes and service with and without screening." Examples reported in Seymore et al. (1997) include the use of different discount rates, none using either the 3% or 5% rates now recommended (Gold, et al., 1996). All used higher rates, typically 7% or 10%. Some studies merge PKU with screening for other illnesses. In two papers the overall cost-benefit conclusion could not be disaggregated into costs and benefits. The studies assumed widely ranging incidence and therefore detection rates, from 1.2 to 17.9 per 100,000 babies screened. They employed different cut-off points for PKU. Three studies did not include in any fashion the impact of PKU on workplace productivity. The studies adopted a wide range of estimates on the duration of dietary treatment, from 2 years to 20, with none assuming life-time treatment. Regardless of these variations, however, all the studies find substantial net economic benefits associated with newborn PKU screening. That is, independent of any health benefits from PKU screening, the costs of PKU screening are substantially less than the averted economic costs from such screening. (Three of the studies conducted a range of sensitivity analyses and in all the sensitivity analyses PKU screening still remained with a positive social economic impact.)
A detailed economic analysis of PKU screening by the Office of Technology Assessment (OTA) (1988) is summarized below. Based on time studies in hospitals, OTA estimated the direct cost of collecting a blood specimen for Guthrie analysis to be $6.07 in 1986 dollars, with a range from $3.88 to $8.16 based on data from three states. OTA estimated that the additional cost of the special diet was $2,914 per year in 1982 dollars (OTA assumed it would be taken for 20 years). OTA assumed that 64% of individuals with PKU would be institutionalized from age 5 to 70, at a cost of $36,500 per year per patient in 1982 dollars. OTA estimated that 18% of individuals with PKU would require foster care, at a net cost of $4,000 per year in 1982 dollars (deducting $5,000 in the personal consumption expenditures that normally would have been incurred). OTA estimated that 36% of individuals with PKU required residential care and services, at a cost of $12,000 per year. OTA estimated that 64% of individuals with PKU would have severe mental retardation and have special educational costs of $84,000 over their lifetime (undiscounted). OTA estimated that 20% of individuals with PKU would have moderate mental retardation and require $75,000 in special education costs. And, OTA estimated that 16% of individuals with PKU would have mild mental retardation, at a cost of $43,000. All of the above costs are in 1982 dollars and were converted by OTA to 1986 dollars.
OTA estimates that newborn PKU screening results in a net societal economic savings of $3,218,000 for every 100,000 screened infants. The net benefits per identified case of PKU is approximately $93,000. OTA conducted sensitivity analysis on a range of their parameters and in no instance were the net economic benefits below $0.
OTA did not take into account any value associated with lower length or quality of life impacts. Nor did they consider the impact of PKU on the productivity of the individual with PKU or his or her parents. This discount rate chose was 7%, much higher than recommended in Gold et al, 1996. All of these are "conservative" assumptions, and relaxing them would only lead to the conclusion that PKU screening is still more cost-effective.
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