Inclusion of Whole-Genome Sequencing with Parental Consent
With the advent of the public health program of Newborn screenings, many metabolic deficiencies such as phenylketonuria (PKU) were caught before permanent damage was done to the child. Newborn screening is offered in every state. Most states have mandated screenings which are done routinely on all newborns, without informed consent being obtained from parents. Whole-genome sequencing (WGS) is increasingly being used in clinical practice and there is interest in adopting it as an adjunct to newborn screening. 1
Newborn genomic sequencing or WGS is an approach to gather and evaluate huge expanses of DNA sequence data. Genomic sequencing is at present being used to test for genetic disorders in adults and children. The use of this technology has been proposed to screen newborns for health conditions they may have or at risk of developing in the future. As the curiosity to WGS grows, investigators and ethicists have acknowledged probable social, ethical, and legal problems that need to be addressed before the WGS is universally implemented. 2
My belief is that states should adopt universal whole-genome sequencing in addition to standard newborn screening. However, unlike the newborn screening, consent should be given by the parents. Reasons for this stance include the cost effectiveness and projected healthcare costs along with taking into the patients’ personal feelings if the detected disease has no treatment.
On one side, being able to obtain WGS information for every child born would increase the amount of data available to better understand how differences in DNA and differences in copies of DNA affect diagnosis and risk of disease. Often times the lack of data hinders how well we understand these things. But this would quickly generate a large sample number. I think that implementation of WGS will take several year since it raises many questions such as be how the data would get stored? Who would analyze the mass amount of data? Would we put into use computers and bioinformatics technology to quickly screen through the data? Also how would the idea of copy number variation (CNV)3 impact how the results get interpreted. Again, how would this information get used? With the increase of improper data storage and breaches in personal information, what steps would need to be taken to ensure this information does not fall into the wrong hands and is not used improperly? 4
The idea of newborn screening is to detect rare diseases and prevent them from doing irreversible damage to a baby’s development before symptoms appear. It is the largest genetic screening program in the United States, with approximately four million infants screened yearly. Newborn genetic screening was started by Dr. Robert Guthrie when he established a blood test to identify raised levels of phenylalanine in newborns with PKU.5 If PKU was diagnosed, mental impedance could be evaded by placing the newborn on phenylalanine-free diet.1 WGS allows for rapid diagnosis and early implementation of therapy for genetic illnesses for which early intervention reduces disabilities and death. The process starts with a small amount of blood from the baby’s heel and smeared on a card. The sample is sent to a lab to be analyzed. The blood sample can be tested for more than thirty disorders. The exact number depends on what state you live in. There is no need to contact the parents’ of the normal screens, but if a rare disease is suspected the parents’ are notified immediately. It is extremely important to detect the disease within the first few days of birth so the doctors can decide the best course of action.
The newborn screening program has been very successful, leading to the diagnosis and treatment of many newborns that would have developed medical morbidity. Historically, the number of conditions detected by newborn screening varied dramatically from state to state; however, most diseases had an acceptable and effective treatment or other intervention (such as dietary restrictions for phenylketonuria) that could prevent or improve the disease. Universal screening without parental permission6 was therefore justified on the basis of the Best Interests Standard. The best interests standard states that affected newborns had a great deal to gain from early diagnosis, with the only risk being a false-positive result.
However, false-positive results do have real emotional and social penalties for the patient’s families. For example, children who had false-positive results were twice as likely as children with normal newborn screening results to have been hospitalized for unrelated symptoms, years later. This suggests that the parents remained hyper-vigilant about their children’s health. Even though early detection can improve quality of life or even save lives, the test also has a high percentage of false positives.
Another consideration is how providers will to relay information to patients. I know that often times, genetic counselors for instance, worry less about results that are more uncertain (usually newer genes where there is little data to support) so that they do not unnecessarily worry a patient.
The state-mandated newborn screening raise policy questions about the innate disparities in the US health system. Every test that results in a positive result calls for counseling along with follow up testing to confirm the diagnosis. These false positives therefore add to the burden of screening programs financially and causing emotional distress to the parents.1 All of these issues limit the success of this hypothetically lifesaving tool.
Whole genomic sequencing would not replace standard newborn screening, instead it would permit physicians to identify disorders very early on. WGS would increase the amount and range of illnesses and conditions that could be diagnosed right after birth. Physicians would potentially be able to intervene and initiate treatment as soon as possible preventing irreversible damage.
A consideration against WGS is that some genetic changes will not only affect the newborn but also their family members. Another fear is that since the analysis of genomic data is constantly changing, it is uncertain whether some changes in the genome are germane to a person’s well-being or not and might be deemed a waste of time. Increasing the sample number would help better understand those differences in the genome from person to person and help increase the accuracy of these types of testing in the future. Still, another consideration is the fact that newborns cannot provide informed consent, which is usually necessary when testing for adult-onset diseases.
Screening is a state responsibility. Each state chooses which diseases to screen for. Some diseases like PKU and congenital hypothyroidism are always tested. Other common diseases screen for are Amino Acid metabolism disorders, Cystic Fibrosis, Fatty Acid metabolism disorders, HIV, Organic acid metabolism disorders7, sickle cell disease. The confusion is that every state runs different tests. The shortcoming of this method is that if an infant is born in a state that does not screen for their disease, they will fall through the cracks and intervention would not be possible for them. This is called geographical inequity.
On one hand there are people who are strong advocates for genetic testing to for personalized medicine.8 Dr. Francis Collins, a distinguished geneticist, previous head of the Human Genome project, and the current Director of the National Institutes of Health states that cheaper DNA Sequencing will make personalized care routine. 9
Genomic Medicine is a planned methodology to disease diagnosis and management that makes use of genome sequence information. The objective is to decode genomes to diagnose diseases better and help choose the best treatments. The aim in making an intervention within the first three months of life is to ensure that the most harm to the child will be prevented. Testing could quickly demonstrate weather a change in the diet is needed, or if medication, hormone given.
Although non-selective WGS for newborn screening may seem unnecessary, selective WGS screening has been proven beneficial by previous studies. Cost analysis reveals that WGS could be cost-effective and cause improvements in the quality of life and expectancy of the affected children.
As of late, experts in the field of genetics, public health, and health policy initiated a set of recommendations to help inform and guide physician, policy makers and scientists regarding the use of genome sequencing technologies in newborn screening. They stated that the main goal of newborn screening should be the identification of gene variations that are of preventable or treatable conditions.
One advantage of whole genome sequencing is that it can identify the genotype before phenotype fully manifests. It can diagnose or rule out known mutations. By having the patients’ whole genome at one’s fingertips, one can reduce unnecessary tests and empirical therapies.
With whole-genome sequencing, it is possible to screen babies at birth and to generate a map of their key genetic markers, or entire genome. The newborn’s genetic information could then be securely kept for future use. The genomic information could then be used throughout the patients’ lifetime to create personalized treatment regimens as additional data becomes accessible about how our genes affect our possibility of developing a specific disorder and how each person’s body reacts to certain treatments. I feel that this could even help identify predisposition for things like addictions – if you know from a young age that you are more likely to become an alcoholic, would you be more likely to stay away from it? Or could it lead to the implementation of early counseling or something like it for high-risk patients? In a sense it seems that these advancements in medicine and technology would be great but they may require an overall reconstruction of our healthcare system.
On the other side, social scientists fear that the use of genetic information could be used to alter the social structure and turn it into the geneticization of social life in which genetics will take over. The term ‘geneticization’ describes a practice where there is a growing predisposition to use genetic justifications to label differences between people and groups.10 Potential discrimination is a big concern among geneticists. Many fear the negative impact genetic discrimination could have on social approval and general confidence in health systems.11 Secondary or incidental findings are very likely when WGS is performed. For example, one can discover that the patient is at high risk for a future illness that was previously unsuspected, or that an asymptomatic patient has a disorder, and finally that a patient is a carrier of a certain disease.
Reasons for implementing WGS are that sequencing could also determine the cause of disorders identified through point-of-care testing, confirm disorders known via other screening methods, assist in providing diagnosis and proper treatment, and offer family testing options about possible disease variants. 2
Previously, whole genome sequencing was too expensive but since the cost is projected to continue to decline, it would be a great investment in the patient’s future. We would be able to monitor trends and potentially intervene. It could also be interesting to see how a person’s DNA changes. Newer testing abilities have resulted in instances where they compare the DNA of a tumor to that of a somatic non-cancerous cell. If the patient’s genome is already known, it would provide a basis of information that could allow for further analysis or comparisons. Genomic sequencing offers a powerful diagnostic tool for patients who show symptoms of a disease involving a single gene and the prospect to detect health conditions before their development. The development of next-generation sequencing (NGS) tools has significantly reduced the price and time necessary to sequence a human genome. It now seems probable that whole-genome sequencing could have prevalent availability in the clinical setting in pediatric care. 2 These advances have led some to believe that the use of NGS will change the existing medical field and public health by allowing more precise and cost-effective genetic testing. 12
Studies conducted in Bulgaria were aimed to assess the attitudes and opinions on the potential use of WGS in conjunction with the traditional newborn screening. The research was conducted via online surveys to pediatricians and geneticists. The study was established on the model of non-selective WGS for newborns and investigation of all genes. The results showed that half of the pediatricians surveyed supported population-based non-selective WGS in newborn screening, while 65.2% of the geneticists conveyed apprehensions.
Most participants emphasized that ethical matters were as significant as medical reasons. They also suggested better security of the patient’s personal data to prevent any abuse by improved genetic counseling and physiological support. Selective WGS could bring improvements to the current newborn screening initiatives. 11
Some potential risks with WGS are discrimination, psychological stress, and invasion of privacy. One respondent stated support for the progress of medicine, but stressed a patients’ right of autonomy and parents’ power not to consent even if WGS is made part of newborn screening.11 WGS also brings to light the matter of patient privacy. If the genomic data becomes part of the medical record, it allows for potential genetic discrimination. Genetic discrimination has moral and ethical implications. For example, in the early 1900s people in the US who were mentally retarded were involuntarily sterilized.13
In the United States, the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children endorses fifty-seven conditions for screening, thirty-one of which are considered core disorders to test for and twenty-six secondary disorders.14 Some critics argue that the suggested extension of newborn screening is occurring quickly. It has been criticized for not conforming to current criterions of evidence-based decision making. It has been advised that the panel also include conditions that do not immediately need treatment in the newborn period, or for which no proven treatment is available. 12
Financially, the use of WGS will only be cost effective when a definite minimum amount of genetic variations are included. The sequence generated at birth would be used for further medical investigations during the patient’s lifetime. The assessment of the cost and benefit of using WGS and sequencing methods becomes much more complex than just examining the costs and benefits attained at birth and in early childhood. One needs to consider the cost, interpretation and storage of the genomic information. Also one should consider the cost of follow-up or confirmatory testing. 12
Before implementing universal genomic technologies one should discuss the role that policy makers may have in considering the implications of incorporating genome sequencing into newborn screening as well as more fundamental issues related to the public understanding and misunderstandings of the part of genetics in influencing health status. Other factor that will impede the integration of WGS into standard newborn screening practices is the impact on insurability, how such screening programs might influence society’s view and understanding of health, and the prospective disparities between countries that can afford to use WGS and those that can’t. According to an article discussed in our ELSI section, Americans were apprehensive that the expansion of genetic tests and then making said tests mandatory would take away an individual’s right to privacy and eventually lead to discrimination. The individual’s genetic information could be used by insurance companies as a vetting tool. Moreover, insurance companies could decrease benefits, increase premiums or flat out refuse healthcare coverage.13
Even if only targeted genome sequencing is adopted, a way of obtaining informed consent for new newborn screening will have to be implemented. Physicians have a duty to provide the crucial information but also increase participation rates by telling the parents that the main focus of newborn screening is the finding and treatment of the disorders in asymptomatic newborns. They should also not neglect to inform the parent about the likelihood of discovering unsolicited results, along with potential research uses of the genomic data and samples. 12
In summary, since Newborn Screening was so successful in identifying diseases to allow for intervention, the next obvious step would be to add whole genome sequencing. Although in the past this was limited due to cost and feasibility, the emerging technologies are reducing the cost of genetic sequencing. By having the genetic information at hand a patient can receive personalized medicine. Unlike Newborn screening, parents should be able to opt in since knowledge of genetic disorder that has no cure could have damaging emotional consequences. Personalized medicine appears to be the present long term goal. With the advent of DNA and other technologies it is bound to happen in some scope. One question I want to raise is the issue of scalability. The current model of a physician treating patients one-on-one would not scale to the demand of personalized medicine. Some other model such as self-care, will need to be implemented to make personalized medicine feasible. The accessibility of cheap and efficient genome sequencing technology, can lead to a medical scene in which each baby’s genome is known from birth and a lifetime of personalized medicine.
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