THE CONTINUUM FROM SERVICE TO RESEARCH
There is a feedback from service to research and back to service, said Anne Comeau, in which research to improve newborn screening, public health, or basic science has led to advances in the other endeavors. A well-known example of this type of beneficial relationship was the study of HIV seroprevalence in childbearing women, a national study that started
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary 3 Uses of Residual Newborn Screening Samples in Research Important Points Highlighted by Speakers A feedback exists between the service of providing newborn screening and subsequent research for biomedical and public health purposes. Residual newborn screening samples have been used in the past for a wide range of useful and productive research. The number of potential uses of residual specimens has increased dramatically as new technologies have developed. Future research will only increase the value of these specimens. Combining information from newborn screening programs with other health data could greatly improve the delivery of health care, although difficult issues of privacy, security, and technological coordination need to be resolved. THE CONTINUUM FROM SERVICE TO RESEARCH There is a feedback from service to research and back to service, said Anne Comeau, in which research to improve newborn screening, public health, or basic science has led to advances in the other endeavors. A well-known example of this type of beneficial relationship was the study of HIV seroprevalence in childbearing women, a national study that started
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary in Massachusetts (Gwinn et al., 1991; Hoff et al., 1988). In the study, the state was divided into nine regions with the residual dried blood spots being identified only by the region where they were collected. All of the blood spots were analyzed simultaneously to determine the seroprevalence of HIV in the nine regions, which ranged from 11.6 percent to 0.3 percent. Thus, by performing research on the dried blood samples collected for the purpose of newborn screening, public health programs in Massachusetts were able to use this information to determine where to locate HIV services for women of childbearing age. Research to benefit the service of providing improved newborn screening can also lead to a direct public health benefit. One recent study on expanding newborn screening in Massachusetts was aimed at identifying children with severe combined immunodeficiency (SCID). The treatment for SCID is quite effective, so a screen to identify such babies is easily justified. However, the practical issues of instituting such a screen on a population-wide level at the time were unknown. To date, Comeau said, the program has screened more than 75,000 infants for SCID, with less than 1 percent of parents declining to participate. Researchers also retrieved residual dried blood spots from storage after having received consent from the parents of infants who had previously been identified with SCID in order to demonstrate the clinical validity of the screening test. “Without the input from our program to save these [residual] dried blood spots, this would not have happened,” Comeau said. The program provided data to the SACHDNC so that the committee could make evidence-based decisions, and ultimately it helped to add SCID to the national uniform screening panel. This interplay between service and research is reflected in the several rationales for retaining residual specimens that Comeau cited from the Massachusetts Department of Public Health Policy on the Purpose, Storage, and Use of Specimens Residual to Those Collected for Newborn Screening Services. These samples provide legal accountability for reconfirmation of newborn screening test results and for the existence of a specimen and its adequate collection. They allow for continuous improvements in the quality of screening and testing methodologies. They enable the comparison and validation of new analytical methods. They provide for research that can advance newborn screening efforts as well as other areas of public health medicine. They make possible basic research to enhance general medical knowledge.
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary However, there are certain issues that need to be taken into account in order to make it feasible to perform this type of translational research. It is not cheap to develop and maintain repositories of dried blood spots, Comeau observed. Specimens need to be stored properly and studies need appropriate quality control. Intensive data management is needed to ensure that the proper consent is obtained and that consent is matched with the correct dried blood spot. State rules for review by independent boards need to be observed and studies sometimes need to be redesigned in response to input from newborn screening personnel. Comeau recommended against establishing central, regional, or national repositories for newborn screening specimens. The states have good track records of stewardship, she said. Control should reside within the communities that have put forth the effort to store specimens so that they can be of value to research. “Just storing specimens is not good enough,” Comeau said. “Do you want quality research? It is a lot of work to have appropriate repositories, with appropriate linkages, and with appropriate [institutional review board] (IRB) evaluation.” As an alternative to centralized repositories, Comeau suggested a virtual repository model in which the physical location of samples, the location of information about samples, and the stewardship or control of the samples are distributed among individuals, the state, and the federal government. PAST AND PRESENT USAGE According to Kenneth Pass, senior research scientist with the New York State Department of Health’s Wadsworth Center, the range of uses for and the population coverage of newborn screening samples make the samples irreplaceable. More than 160 uses have already appeared in the scientific literature and many more will be developed in the future. Residual dried blood spots have been utilized for research with informed consent, with an opportunity to opt out, as anonymized, and as de-identified (consent is discussed in Chapter 5). “Are there ways to use them? Have they been used? Have they been reported? Yes, yes, and yes,” Pass said. Sharon Kardia, professor and chair of epidemiology at the University of Michigan and co-director of the Michigan Center for Genomics and Public Health, listed some of the key attributes of residual dried blood spots. They provide a nearly complete representation of the population. They can be integrated with existing public health data. Because they consist of whole blood samples, they also contain a very wide range of biomarkers, including DNA, RNA, proteins, metabolites, and evidence of exposures to environmental or infectious agents. Although some analytes, such as proteins, degrade over time, Kardia said that, in general, the extent of preservation is astonishing.
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary The potential for residual newborn screening samples to be used in research has been recognized for many years, Pass noted. While no genetic tests are currently performed as part of the initial newborn screening process, many research applications could make use of the inherent genetic matter present in these samples. In 1996, he and a group of colleagues wrote, “Potentially these samples provide a genetic material ‘bank’ for all newborns nationwide. Their value as a resource for other uses has already been recognized by scientists, administrators, and judicial officials” (Therrell et al., 1996). Since then, as the field of human genetics has developed, the value of these samples has become even more apparent. They represent an unbiased sample of biological materials from the entire United States and much of the industrialized world. They cover nearly the entire population and often are the only remaining tissue sample for a particular individual. “Each of us has his or her own story about how a blood spot was used postnatally [or] after death to help with the diagnosis of a child,” Pass said. Samples have been particularly useful in public health studies, Pass said. They were used to identify PCB hazards for children born near Love Canal in New York and research on this topic is still under way at the Wadsworth Center. They provide markers for fetal alcohol syndrome, drugs that the mother might have taken during pregnancy, and environmental exposures that the mother may have experienced. (For examples, see Burse et al., 1997; Henderson et al., 1997; and Spliethoff et al., 2008.) In particular, they can be used to detect exposures to perfluorinated compounds, cocaine, nicotine, caffeine, hepatitis B, toxoplasmosis, syphilis, rubella, pesticides, E. coli, and other harmful drugs and infectious organisms. The DNA that can be extracted from residual dried blood spots is also valuable. It can be used as a second-tier screening mechanism to confirm results from other biomarkers in diagnosing such disorders as cystic fibrosis, sickle cell disease, and galactosemia. DNA samples can be used to determine how common a particular genetic variant is in the population and enable new discoveries related to specific diseases. For example, Pass and his colleagues recently published a paper on new candidate biomarkers for autism and nine of the markers were identified in residual dried blood spots. Blood spots also have found applications in forensics. “Again, we all have a story of how these specimens have been used in natural disasters or terrorist attacks to establish a positive identification,” Pass said. Alan Fleischman also commented on the wide range of uses for residual newborn screening samples, both for public health purposes and for research directed toward individuals. The gradual expansion of these uses has had a major effect on public health programs, he said. Newborn screening programs were originally small. Departments of public health did not have a sense of being powerful, but they had high-quality people dedicated to their work in the midst of a complex state public health structure.
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary The first research applications were consistent with the agencies’ efforts to improve public health. Surveillance for threats to public health using residual newborn screening samples was a natural part of what a department of health would do. Such surveillance was based in its mission and was not controversial. As researchers outside departments of health began to recognize the value of residual newborn screening samples, they began to seek access to these samples. And because the people in these departments were thoughtful and believed in research, and because the questions being asked by researchers were reasonable, they began to build relationships with the researchers. Today, the most important question regarding residual dried blood spots, according to Fleischman, is whether they can be stored and used for future research without jeopardizing the important public health goals of newborn screening programs. “My answer is yes, as long as we are careful,” he said. RESEARCH POTENTIAL OF RESIDUAL NEWBORN SCREENING SAMPLES Kardia noted that modern technologies make it possible to measure and evaluate many different molecules and genes simultaneously. Genetic material can be amplified, turning tiny samples into samples large enough for analytic techniques. Thousands of genetic variants can be detected in residual dried blood spots collected years before. Dried blood spots represent “a huge repository of information about biomarkers and molecules that are associated with health,” Kardia said. As an aside, Kardia noted that dried blood spots have proven so useful that they are being used outside of newborn screening. Pharmaceutical companies are beginning to collect dried blood spots as opposed to venous blood samples to test for the presence of particular molecules and to determine the efficacy or toxicity of drugs. Vaccine trials in developing countries use them for monitoring. Some epidemiological researchers are moving to dried blood spots for measuring environmental exposures. Dried blood spots are even being used to gather biological information about animals used as model organisms for medical research. Very valuable forms of research can be conducted using only anonymized samples, but the information in a dried blood spot can be particularly valuable when it is combined with other sources of data, Kardia said. Birth records, death records, immunization data, hearing test results, nutrition programs, cancer registries, Medicaid records, and other types of public health information can all be integrated with the information derived from dried blood spots. Data based on geographic zones, such as water quality,
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary air quality, environmental hazards, disease outbreaks, or hospital discharge records, can also be combined with the information available from dried blood spots. “The integration of these provides real grist for research advances,” Kardia said. Residual blood spots from newborn screening offer a continuum of research opportunities, Kardia said. They can be used for case studies of rare diseases, cross-sectional studies of the prevalence of a particular condition or exposure, case-control studies, and birth cohort studies. These last two are particularly promising, she said, because residual dried blood spots make it possible to do such studies across large populations and for many diseases. “Just about any disease that is found in a population could be, in a case-control format, evaluated,” she added. Cross-sectional studies can assess patterns of genetic variations or environmental exposures geographically and assess trends over time. For example, some people have particular genetic dispositions that make them highly susceptible to diseases such as familial hypercholesterolemia. These individuals could be identified and efforts could be made within communities to get them access to care or other interventions. Trends also could be assessed over time using objective measures rather than the recollections of the people in the study, which may not be accurate. “Being able to assess time changes in a population is a huge benefit,” Kardia said. Hundreds or even thousands of diseases and health outcomes could be studied using residual dried blood spots in case-control studies. Examples include cerebral palsy, hearing loss, severe combined immunodeficiency, sudden cardiac death, drug allergies, and childhood cancers. Today, the controls in a study are usually not random and cases have to be painstakingly identified and contacted. Residual dried blood spots offer a way to identify robust and reliable sources of both cases and controls in large populations. Today, birth cohort studies are typically tremendously expensive and difficult to perform, though they offer a powerful way to investigate a population’s health. Residual dried blood spots, if combined with information in public health registries, could provide an integrated picture of the health of entire populations, starting from birth. Such a study would offer a unique opportunity to look at the effects of health policies on health outcomes, for example. Public health registries could be combined with electronic health records to track the development of particular conditions across a person’s lifetime and across generations as well as to determine the effects of interventions. It would also allow for the long-term investigation of environmental accidents and hazards. “There is huge potential,” Kardia said. “We don’t know what next week will bring,” Pass added. “If we have those spots, we are ready to go.” However, Kardia acknowledged that many ethical questions need to be addressed before many of these steps could be taken. “Relationships to the
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary participants or to departments of health are incredibly important, because this whole endeavor is about helping people,” Kardia said. “If I alienate either the participants or the department of health, then I really haven’t done any service at all.” AN INTEGRATED RECORD OF CHILD HEALTH Michele Caggana, chief of the Laboratory of Human Genetics, director of the Newborn Screening Program, and head of the Genetic Testing Section of the New York State Department of Health’s Wadsworth Center, observed that health information technology has progressed to the point where it is possible to have a single health record containing many forms of public health data, such as the results of newborn screening, immunizations, hearing tests, childhood diseases, hospitalizations, medications, exposures, and so on. Today, however, much of this information is kept in separate records. Newborn screening data and vital records data, for example, are not often combined. New York State has begun to take steps to eliminate this separation and establish a unified health record for each child. Known as the Child Health Information Integration (CHI2) project, the effort is being led by representatives in different bureaus of the health department involved in child health. “We want to create a virtual child health profile,” Caggana said. Authorized users involved with the health of a child would have access to certain views of comprehensive information on each child. This information could include newborn screening results, hearing screening results, admissions to a neonatal intensive care unit, immunizations, early intervention programs, other specialized care, testing results, and needs for follow-up (see Figure 3-1). Such a system would have many benefits, Caggana said. It would provide comprehensive, timely, and accurate child health information to support the provision of health-care services. It would ensure that newborn screening tests have accurate diagnoses and that children receive treatment and short-and long-term follow-up as needed. It would help coordinate medical care and public health activities and services. The timely sharing of accurate data would give clinicians a full picture of a child’s medical history and ensure that children receive needed preventive, screening, therapeutic, and follow-up services as well as eliminating duplicate work and services. Such a system would also allow for population-based decision making and would enable evaluations of the newborn screening program. Better policies could be developed, and programs could be better planned and implemented. Over the long term, the CHI2 program will allow clinicians and public health officials to engage in meaningful exchanges of health information. Such exchanges will reduce the reporting burden, help track infants over
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary FIGURE 3-1 The CHI2 vision of integrating public health databases (top) is juxtaposed with the current separated systems approach (bottom) used in New York State. SOURCE: NYSDOH Child Health Information Integration Project; current as of May 2010.
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary time, improve diagnoses, help standardize data and diagnostic criteria, improve public health communication, and improve the quality of care. It could also help in locating missing children and detecting environmental exposures. In the short term, such a system could determine how many infants were born and not screened in New York State as well as how many babies who were screened in New York were not actually born in New York. It could also improve the quality of demographic data, improve tracking and follow-up measures, better track infant deaths, and provide for integrated childhood medical records (see Box 3-1 for an example of the potential use of the CHI2 approach). BOX 3-1 A Use Case for Integrated Information To guide the CHI2 project, a use case was developed to show the system in action. A child is born and admitted to the neonatal intensive care unit (NICU) because of transient rapid shallow breathing and poor oxygen saturation upon delivery. Information about the child is entered into the hospital’s systems and into all of the Department of Health systems that capture NICU and screening data. The child is determined to have no recurrent problem and is transferred to the newborn nursery for routine hospital care. A hepatitis B vaccine is administered, and this information is also logged into the system. Shortly after that, a newborn heel stick is performed, a vital statistics workbook is prepared, and the child receives a hearing screen. The dried blood spot which was obtained is sent to the Wadsworth Center for testing and Dr. Good-friend, the child’s pediatrician, schedules a one-week checkup in her office to see the baby. At approximately 1 week, Dr. Goodfriend is advised that the child had a positive screen for hypothyroidism. She tells the family about this positive result at the baby’s 1-week visit and orders a follow-up test. The necessary blood samples are drawn and sent to the lab for testing. While the baby is in her office, Dr. Goodfriend accesses the CHI2 data system and verifies that the hepatitis B vaccine was administered in the hospital. The test results show that the baby does not have hypothyroidism. Her office calls the family to let them know that the follow-up laboratory tests were within normal limits and that the baby does not have hypothyroidism. The outcome is documented in the CHI2 system. After a few months the family moves to a different county. The child is taken to a new pediatrician, Dr. Wellness, for a 6-month visit. Dr. Wellness accesses the CHI2 system and determines that the child has missed one set of vaccinations, which are then administered. This use case reflects “our perfect-world scenario,” Caggana said. Technology would be used to combine all the sources of information with all the support systems that a patient might require over a lifetime.
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Challenges and Opportunities in Using Residual Newborn Screening Samples for Translational Research: Workshop Summary However, linking information systems raises major challenges in the areas of privacy, legal and regulatory considerations, and technology, Caggana said. The system needs to be secure and to comply with federal and state regulations. Only appropriately authorized personnel should be able to access the data and only for the information which is proper for them to retrieve. New regulations may be needed, said Caggana, to allow data exchange while still protecting patient privacy and security. For example, people working with the CHI2 project have discussed how to maintain security, role-based access, and privacy if records are opened up to parents. Finally, many current technology systems cannot communicate easily with one another. Despite these challenges, not instituting such a system would have much greater drawbacks, Caggana said. Data from electronic health records and regional health information organizations (RHIOs) would be more difficult and costly to use for public reporting purposes. The continued lack of a coordinated approach would make it more difficult for the Department of Health to share integrated child-related data with health-care providers. And practicing clinicians and public health programs would be unable to use existing Department of Health information to improve the clinical and public health outcomes of New York’s children. The long-term outcomes of having such a system are largely unknown, yet the system offers sufficient promise that New York State is vigorously pursuing it.