Menu
Back to Journals » Pharmacogenomics and Personalized Medicine » Volume 12
Pharmacogenomic Testing In Pediatrics: Navigating The Ethical, Social, And Legal Challenges
Authors Haga SB
Received 11 June 2019
Accepted for publication 12 September 2019
Published 14 October 2019 Volume 2019:12 Pages 273—285
DOI https://doi.org/10.2147/PGPM.S179172
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Martin H Bluth
Susanne B Haga
Department of Medicine, Division of General Internal Medicine, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, 27708, USA
Correspondence: Susanne B Haga
Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, 304 Research Drive, Box 90141, Durham, NC 27708, USA
Email [email protected]
Abstract: For the past several years, the implementation of pharmacogenetic (PGx) testing has become widespread in several centers and clinical practice settings. PGx testing may be ordered at the point-of-care when treatment is needed or in advance of treatment for future use. The potential benefits of PGx testing are not limited to adult patients, as children are increasingly using medications more often and at earlier ages. This review provides some background on the use of PGx testing in children as well as mothers (prenatally and post-natally) and discusses the challenges, benefits, and the ethical, legal, and social implications of providing PGx testing to children.
Keywords: pharmacogenetic testing, education, benefit, risk, consent, children, maternal health
Introduction
The expanded interest and implementation of pharmacogenetic (PGx) testing have raised both challenges and excitement alike. As with some other testing applications in personalized or precision medicine, PGx testing can be used for patients and healthy individuals. The scope of testing has evolved from single gene to large gene panels. As with any new clinical application, the development of the clinical delivery infrastructure, education, and clinical decision support of providers and patients, and evidence basis are critical for successful implementation and utilization. In the paper, the ethical, legal, and social issues associated with PGx testing for children are considered in light of the scientific and clinical evidence, particularly during pregnancy and for newborns.
Overview Of PGx Testing
PGx testing involves the analysis of variants of genes associated with drug metabolism and transport or medication targets. The knowledge of potential differences in drug metabolism impacted by genetic variants can inform drug selection or dosing over a patient’s lifetime since the results will not change with age and many of the variants occur in genes involved in the pathways for multiple medications. In particular, the genes encoding liver enzymes in the cytochrome P450 family, including CYP2D6 and CYP2C19, are involved in the metabolism of a wide range of commonly used drugs and are highly polymorphic. Genetic variants impact enzyme activity, resulting in phenotypes defined as ultra-rapid, normal (extensive), intermediate, or poor metabolizer. Thus, knowledge of a patient’s PGx genotype in combination with other clinical information can inform appropriate medication and dosing decisions.1
Some of the early successes with PGx were developed in children, such as with the TPMT gene and acute lymphoblastic leukemia.2–4 The spectrum of potential applications of PGx testing in children ranges from post-transplant5 to pain management6 to psychiatric illness.7–11 Ongoing trials of PGx in pediatric populations continue to gather evidence of clinical utility.12–14 There are a wide range of clinical PGx tests currently available,15 typically including multiple genes (multi-gene panels), though not specific to age group but rather medication class or disease.
PGx testing can either be ordered at the point-of-care (at the time a drug is needed) or preemptively. There is an ongoing debate about the use of preemptive testing and clinical utility.16,17 Clinical benefits will only be accrued if a therapeutic need arises for a medication known to be impacted by PGx variant and if the prescribing decision was informed by the test results (to increase likelihood of therapeutic response or reduce likelihood of an adverse response). Thus, it is likely that not all of the information from a multi-gene panel test will be of benefit to the patient. However, it may be the same or costlier to order a PGx test for a single gene as a panel test since the addition of more genes may not substantially change the effort or cost of testing (economies of scale). Another consideration for ordering PGx testing at the point of care (i.e., when treatment is needed) is the delay in treatment while testing is being completed. Many labs offer a short turnaround time (48 hrs), but that still may not be quick enough for some clinical needs.
It is unclear what the attributable fraction of genetics is to non-response or an adverse response. Clearly, multiple genes encode the many proteins involved in the multiple pathways from drug absorption to drug excretion, some of which have yet to be identified. Furthermore, other factors such as the gut microbiome,18–20 diet, age, concurrent medication use, and co-morbidities all contribute to drug response.21 Thus, for such a complex phenotype as drug response is, it is likely that a single gene only accounts for a small proportion of variability observed in drug response, except in rare cases that mirror a Mendelian disease.
Medication Use In Children
Data from analysis of 2013–14 data from the National Health and Nutrition Examination Survey (NHANES) demonstrate medication use throughout childhood, with about 20% of the children having had at least one prescription medication in the past year.22 Adolescents (13–19 years) had the highest medication use (23%) and infants/toddlers (0–5 years) had the lowest (15%).22 Use of prescription medications in children has declined from 25% in 1999–2002 to 22% in 2011–2014.23 The most commonly prescribed groups of medications were respiratory agents (i.e., bronchodilators), followed by psychotherapeutic agents and antidepressants.22
Adverse drug response (ADR) in children is a major concern,24 due in part to drug use based on limited evidence and the complexity of pharmacokinetic and pharmacodynamic changes that occur during development. It has been estimated that about 8% of the children on medications are at risk for drug–drug interactions.22 Emergency room visits for ADRs in children are primarily due to overdoses (45%), but 13% were due to adverse effects.25 About half of these visits were in children between one and four years of age.25 Children and adolescents may have greater risk of ADRs related to psychotropic medications compared to adult patients.26
Prenatal And Newborn Period
Newborns undergo a battery of tests including those for inherited genetic diseases. Called newborn screening, testing for a suite of inherited conditions can identify affected newborns that, with early intervention, the condition can be prevented or outcomes substantially improved.27 These tests are performed by state public health laboratories, and the number and type of diseases tested vary from state to state. PGx variants are not currently included in any state newborn screening panels. The primary criterion to expand a newborn screening or add a new disease to the screening panel is clinical utility, and specifically, demonstration of the clinical benefit of an early diagnosis.
Newborns may require treatment or be exposed to medications through maternal use during pregnancy and/or the post-partum period through breastmilk.28 Maternal use of medications during pregnancy varies by country, ranging from 28% in Australia,29 97% in the US,30 about 60% in Canada,31,32 79% in the Netherlands,33 85% in Scotland,34 and 95% in France.35 Canadian data show an increase in maternal medication use over the past decade, with 10% more women prescribed medications during pregnancy between 2002 and 2011.36 Common medication classes used during pregnancy include antibiotics, anti-emetics, oral contraceptives, asthma drugs, vitamins, and antidepressants.31 In addition, the burgeoning problem of opioid dependence and substance abuse during pregnancy presents a substantial risk for neonatal abstinence syndrome (NAS), fetal alcohol syndrome, low birth weight, and other conditions.37,38 Treatment with methadone or buprenorphine do not appear to increase risks to fetal development.39–41
There is also a wide range in estimates regarding maternal medication use during the post-partum period, from 34% to 100%,42 with as many as three to four medications used during breast-feeding.43 Many women request pain medications, particularly in the first-week postpartum for discomfort due to episiotomy, perineal laceration, uterine involution from vaginal delivery, or a cesarean section. The most commonly prescribed drug classes are oral analgesics, antibiotics, and vitamins during the postpartum period.44 Mothers and providers may be uncertain about medication use due to concerns about the adverse impact on the newborn’s health; decisions not to initiate or stop treatment may pose risks to the mother’s health.45
PGx variants can impact both safety and efficacy of medications for the mother’s health as well as fetus/newborn’s health.46,47 In addition, physiological changes associated with pregnancy can alter pharmacokinetic states,48–50 including for the cytochrome P450 or CYP genes.51–55 Thus, the combined effect of pregnancy-related changes and genetic variation could potentially result in unpredictable activity levels of key proteins associated with drug response.
In the fetus/newborn, the metabolic pathways are subject to developmental changes, and thus, enzyme activity levels are in flux. A number of medications reportedly used during and after pregnancy are known to be impacted by PGx variants, including medications for nausea,56 prevention of preterm labor,57 opiate maintenance such as methadone,39 and pain.58–60 Predictive models of transfer into human milk thus far have not accounted for maternal PGx variants.28,61,62 Drug toxicity is likely to be more common during the newborn period due to slow metabolism and elimination by the infant.63 Although all medications can enter breast-milk, serum concentration will vary due to characteristics of the drug.64 For example, psychotropic medications are shown to be present at low levels in breastmilk and no data have indicated harm to the infant.65 Low molecular weight and lipophilic medications can easily move through the lipid membranes of cells, and therefore, the concentration of these types of medications in breast-milk is higher than other types of drugs.63
Harms to the newborn associated with exposure through breast milk have been reported infrequently.66 One example of the adverse impact of PGx and medication exposure during nursing is with the enzyme CYP2D6 enzyme, which converts codeine to the active metabolite morphine. The prevalence of CYP2D6 genetic variations linked to ultra-rapid metabolism ranges from 1 to 28 per 100 individuals, varying between racial/ethnic groups.67 Thus, a nursing mother who is an ultra-rapid metabolizer may expose the infant to toxic levels of the active morphine metabolite.68 The use of codeine for pain relief during the post-partum period has decreased,36 likely due in part to knowledge of the impact of CYP2D6 variants on drug metabolism and the reported newborn deaths associated with maternal codeine use during breast-feeding and PGx variants,69,70 and the subsequent US Food and Drug Administration warnings.71
In addition to PGx variations, there are several other factors that impact drug response in children, which can affect dosing and exposure levels.72–75 One of the primary challenges to the use and interpretation of PGx testing in children is the developmental changes in gene expression.76–80 Within the span of a few weeks to months after birth, the levels of drug absorption, transport, and metabolism alter significantly.81 Further complicating treatment decisions and prediction of the impact of PGx variants on drug response, physical changes (body weight, height) and environmental factors, such as maternal smoking, and the child’s diet, polypharmacy, and co-morbidities can affect drug response.24,82–85 Prior medication use also may impact expression of drug metabolism enzymes through epigenetic modifications.86 Given the multitude of factors impacting drug response and ontological fluctuations, it may be helpful to perform both PGx testing (DNA-based) and pharmacometabolomic analysis to generate a more comprehensive dataset for drug response predictions.87,88
PGx Programs In Children
The implementation of PGx testing into practice requires a multi-faceted approach and dedicated delivery team.89,90 There are several ongoing clinical PGx programs in the US, mostly at academic medical centers, in both inpatient and outpatient settings.91–93 Some programs have also been implemented at community health centers.94 PGx programs that are devoted exclusively to children include Medi-Map at the Inova Hospital Center in Fairfax, Virginia,95 Cincinnati Children’s Hospital Medical Center,96 and St Jude Children’s Hospital.97 In addition, other programs are investigating the benefits and risks of implementing newborn sequencing programs, in affected infants in neonatal intensive care units (NICU)98,99 and healthy newborns,100 though PGx genes are not typically included (e.g., the BabySeq program reported including SLCO1B1, associated with response to statins101). PGx results may also be generated from whole exome or genome sequencing tests ordered for diagnostic purposes (a secondary finding).
Weighing The Benefits And Risks Of PGx Testing In Children
Much has been written regarding genetic testing in children in general.102–111 However, fewer papers have been published specifically about the appropriateness of PGx testing in children.76,112–114 Guidelines from professional organizations focus on the benefits of testing to the child103,115 and support the use of PGx testing, particularly when the clinical utility has been demonstrated in pediatric studies.102 For example, the American Academy of Pediatrics states “When performed for therapeutic purposes, pharmacogenetic testing of children is acceptable, with permission of parents or guardians and, when appropriate, the child’s assent”.115 PGx testing could be argued to straddle the definition of predictive testing and predispositional testing,103 since with exposure to a specific medication, the phenotype may or may not manifest depending on the extent of the clinical and genetic heterogeneity (and in the absence of exposure to a specific medication therapeutic, the phenotype will not manifest). Post-ADR, PGx testing may be considered diagnostic.
Public attitudes toward PGx testing are generally positive, though familiarity with or awareness about testing has not been reported high.116–118 In weighing the benefits and risks of PGx testing in children, a wide range of factors should be considered including test characteristics, benefit and risk to pregnant mothers, benefit and risk to the fetus/newborn/child, testing logistics including sample collection, storage and portability of test results in the medical record, access to testing, provider preparedness and clinical decision support, and patient education and informed consent. The testing scenarios – whether testing is medically necessary (at the point of care) versus optional/elective (preemptive testing) – will impact the balance of benefit and risk and decisions regarding the appropriateness of testing in children.
Benefit/Clinical Utility
Evidence supporting the use of widespread PGx testing of children has not been reported, but rather, reports of specific medications or classes have suggested some benefit of PGx testing for children.119–123 If evidence continues to accumulate for different pediatric medications, it is likely that this will be used to support the use of preemptive PGx testing in children along with data documenting the increasing use of medications in children. Thus, currently, the benefit(s) of PGx testing in children with respect to specific medications in need are more straightforward than preemptive testing of healthy children since the time to benefit and the benefit for the medications to be prescribed are not known. To date, no studies have demonstrated benefits of PGx testing of the mother prior to or early in pregnancy, but such knowledge may inform medication use during pregnancy. Although the occurrence of severe infant drug toxicity due to transfer of drug metabolites via breast milk appears limited,66 PGx testing to prevent even these uncommon events and alleviate maternal concerns of newborn drug toxicity may be worthwhile given the long-term benefits of breast-feeding. In addition, maternal PGx status will also be useful during the post-natal period. However, the utility of this information may be limited without knowledge of the infant’s PGx status and also due to limited lactation studies regarding drug concentration in human milk and milk-to-plasma concentrations.
In addition, psychologically, parents may benefit from reduced anxiety regarding risk of ADRs and efficacy of treatment plans for their child and increase compliance with the prescribed regimen, thereby improving likelihood of desired health outcomes.
Risks
There are currently 261 drugs listed on the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling (https://www.fda.gov/drugs/science-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling); 136 (52%) are approved for pediatric use.124 However, an earlier study reported a small proportion of the 65 of 150 with medications approved for pediatric use between 1945 and 2014 and that included with PGx information in the approved drug labeling was based on data collected through pediatric PGx studies (9 of 65).125 To further demonstrate the limited availability of data from pediatric PGx studies, a recent search (conducted 9 June 2019) of the US National Library of Medicine’s PubMed database shows that the majority of PGx clinical trials (1028/1297 or 79%) are conducted in adults compared to children.
Therefore, the largest risk is the inability to interpret PGx results given the limited amount of evidence to interpret the clinical significance on risk of ADR or likelihood of response. Similarly, for some medications, there are less data regarding pharmacodynamic and pharmacokinetic properties in children compared to adults. The interpretation of PGx data may be more challenging in children due to developmental changes in gene expression and physiological changes that impact other drug absorption, transport, and excretion children.126 Gene expression or enzyme activity assays may provide more additional insight to inform treatment rather than DNA-based testing. In addition, much of the research conducted on PGx has been with individuals of European ancestry, and therefore, there are limited data for minority populations,127 though it has been demonstrated there are differences in allelic prevalence between groups.128 As a result, the clinical utility of PGx testing may be lower in minority populations as the prevalence and clinical significance of PGx variants are still being investigated in these groups.129–133 Depending on the type of testing platform used or choice of variants to include, some rare variants or variants that are more prevalent in certain populations may not be captured or included in a clinical PGx test. In addition, although some medications are used in both pediatric and adult populations, evidence of PGx testing benefits generated in an adult study population may not extrapolate to a pediatric and caution should be taken to develop a pediatric PGx program based on adult findings.11 With the rapidly changing test technologies, the scope of testing may not be limited in the future.
Sample collection may also be a concern for children. Parents may not consent to blood draws for their children and/or providers may not recommend testing because of the blood draw.96 Many labs now offer testing on buccal swab or saliva samples. At this time, prenatal PGx testing of drug metabolism genes would likely require a fetal specimen from chorionic villus sampling or amniocentesis. Given the risks of these invasive procedures, prenatal PGx testing should be limited unless there are known serious adverse consequences associated with maternal medication use. However, with the rapid expansion of non-invasive, cell-free fetal DNA testing,134 single gene or multiple gene PGx panel testing may be possible in the near future. Some data have indicated that maternal medication use may impact the quantity of cell-free fetal DNA available.135
Children and family members may be at risk of psychological harms resulting from learning of a PGx variant that can affect how the child responds to medication. Parents may experience anxiety, stress, and feelings of hopelessness if their child is found to have an extreme phenotype (e.g., ultra-rapid or poor metabolizer) or not have the genetic variation indicated for an available medication. Heightened concern for adverse exposure could lead to poor adherence or avoidance of medical care in extreme situations. Additionally, misconstrued fears that the child will not benefit from medications may also affect parents’ behavior toward their child, treating them as highly vulnerable or at risk and potentially limiting interactions or participation in childhood activities to reduce the likelihood of illnesses that require treatment.136 Since the effects of a PGx variant may never manifest without exposure to certain drugs, curtailing childhood activities may cause more harm than benefit. Furthermore, feelings of stigmatization and anxiety may be experienced by family members and the child, even though the phenotype may never manifest due to other clinical and genetic factors (some unknown) or lack of exposure to medications impacted by that genetic factor. It is important to note that no evidence to date has reported on any of these potential risks with PGx testing in either pediatric or adult populations. Positive PGx results will also have implications for siblings and parents, potentially leading to PGx testing of family members.
In the absence of immediate benefit, some may argue that preemptive testing should not be ordered for healthy children (in line with recommendations for predictive testing103). Alternatively, if treatment is not needed, preemptive PGx testing could be deferred until the child is of an age and maturity level that they may participate in decisions regarding testing.102 However, if treatment is needed and impacted by a PGx variant, it could be worthwhile to order a panel test that would provide benefit both for the immediate and long-term health of the child.
Another risk that has been raised with PGx testing is the association of some genes with unrelated disease risk or phenotype. For example, the ApoE4 gene is associated both with cholesterol metabolism and response to statin medications as well as Alzheimer disease.137,138 The American Academy of Pediatrics states that “If a pharmacogenetic test result carries implications beyond drug targeting or dose-responsiveness, the broader implications should be discussed before testing”,115 echoed by the American Academy of Pediatrics and American College of Medical Genetics and Genomics joint statement.103 The potential for genetic discrimination also exists, although discriminatory actions by employers and health insurers are prohibited by the federal Genetic Information Non-Discrimination Act (GINA).
Informed Consent And Patient Education
Given the novelty of PGx testing, informed consent or physician assent/acknowledgment that the parents have provided consent for testing is typically required.139 For adolescents and young adults, their preferences regarding testing may not always be supported.140 Thus, some discussion and educational resources should be available to parents to promote informed decision-making as well as for older children that have reached a level of maturity to provide assent. For example, Cincinnati Children’s Hospital has developed patient education sheets for each test offered (www.cinncinnatichildrens.org/gpsinfo). Other groups have developed videos to convey some of the complex scientific and medical concepts.141 In particular, given the multitude of factors that can impact drug response, parents and children should understand that PGx testing will provide some insight about drug response, but that the results should not be considered absolute in most cases. Furthermore, the ongoing research may alter the interpretation of PGx results. If considering preemptive testing, testing could be delayed until late adolescence or adulthood when the patient can provide assent or full consent, respectively. Various educational tools used for genetic testing could be adapted for PGx testing to promote parental awareness and decision-making.142
Provider Support
Several studies have reported limited knowledge of providers regarding precision medicine and PGx, though none have specifically evaluated knowledge of obstetricians or pediatricians.143–150 While some literature indicates inclusion of precision medicine and PGx in medical curricula,151–153 it is unclear how consistent or to what depth this subject is taught. In some cases, patients may share PGx results ordered by specialists with their general pediatrician, who may not be prepared to integrate the findings into practice, and online resources about PGx are not easily located through search queries.154 Thus, to address knowledge gaps and acknowledge varied learning styles, multiple modes of information delivery are likely needed to increase providers’ knowledge and comfort in delivering PGx testing, such as immersive learning opportunities and traditional continuing medical education (e.g., workshops, online modules, print).155,156
While there are a number of comprehensive PGx resources, these may be overly technical for general practitioners.157–160 At the point-of-care, clinical decision supports have been developed at several medical centers to inform providers about the availability of PGx testing for certain drugs that are prescribed or alert providers of the patient’s test result if testing has already been performed.96,161–166 PGx testing reports can also be a source of information, including treatment recommendations based on genotype.167
Beyond physicians, nurses and pharmacists can also play important roles in the delivery of PGx testing, patient education, and insuring appropriate use of results. Nursing and pharmacy educators and schools have recognized training needs and are working towards integrating content into curricula and other learning opportunities.168–171 Pediatric pharmacists can help integrate PGx results into therapeutic decision-making and work with both providers and families.172 In some places, clinical PGx consultation services have been established.96,173 It is unlikely that genetic counselors will play a central role in the delivery of PGx testing given the limited number of counselors available and the different clinical settings in which they are traditionally accessible. However, counselors will likely encounter PGx results in sequencing and should be prepared to discuss these with patients and patients with complex results should be referred for counseling.174
Storage And Portability Of Results
Particularly for children and the anticipated recurrence of the use of PGx information throughout their life, the storage and portability of PGx results are critical. The integration of PGx information into electronic health records has been investigated over the past several years and several groups have developed standardized nomenclature175,176 and test results reporting. As the child reaches adulthood, it will be critical to insure that the PGx results are transferred to the adult care providers.
Regulation And Reimbursement
While the evidence regarding drug safety and efficacy in children has increased due to more regulatory requirements and incentives, there are still challenges in conducting and completing pediatric trials.177,178 The oversight of clinical laboratory testing has also been the subject of much debate and scrutiny over the past several decades. Many genetic tests, including PGx testing, are considered a ‘laboratory-developed test’ (LDT) and at this time, the FDA typically does not enforce premarket review179 and only a few test manufacturers or laboratories of proprietary tests have obtained FDA approval for PGx testing. In addition, the direct-to-consumer company 23andMe received FDA approval in 2018 to market a multi-gene PGx test panel,180 though this has been available in the UK.181 However, the agency is taking more interest in the clinical validity of PGx testing and potential risk for harm through issuance of safety alerts and warning letters to a clinical laboratory. In November 2018, the agency released a safety alert to patients about PGx testing and the limited evidence basis, urging patients not to make any changes to their medications without consulting a health provider.182 In April 2019, the FDA issued a warning letter to Inova Genomics Laboratory, which was providing PGx testing to newborns among other PGx tests.183 The agency raised concern about the evidence of clinical validity and potential harms to patients if results are used to inform treatment decisions. All testing laboratories based in the US must comply with the Clinical Laboratory Improvement Amendments (CLIA) that require documentation of analytical validity, quality controls and assurance, personnel qualification and some evidence of clinical validity.
At this time, in the US, reimbursement for PGx testing is inconsistent and guided by the availability of clinical trials data and clinical guidelines, which are still lacking for most tests.184 A few cost-effectiveness studies have been performed for PGx testing for children185 and mothers,186 although the majority have focused on adult applications. There are no national coverage decisions for PGx testing in the US. Preemptive PGx testing is often not covered by insurers187 and, therefore, is an out-of-pocket expense, resulting in limited access and disparities. Patients have expressed willingness-to-pay for testing to reduce risk of serious adverse drug responses, though the amount was impacted by their overall interest in testing.118,188–190
Conclusion
The short and long-term benefits to children (and potentially expectant mothers), the growing body of evidence, and the declining costs of testing technologies for multiple genes should positively influence uptake of (or utilization) testing. However, the clinical utility of PGx results is likely to remain limited until more pediatric PGx trials are conducted and a greater understanding of the multiple factors that can impact drug response is attained, especially in younger children who have not attained stable expression of many genes important to drug metabolism and transport. PGx test results may inform the safe use of medication during pregnancy and post-partum, and increase mothers’ confidence that breast-feeding is safe for their infant. As PGx testing is still novel to many providers and patients, more efforts are needed to improve awareness about testing, promote informed decision-making, and insure appropriate utilization and access.
Disclosure
Dr Susanne B Haga reports grants from US National Institutes of Health, during the conduct of the study. The author reports no other conflicts of interest in this work.
References
1. Aka I, Bernal CJ, Carroll R, Maxwell-Horn A, Oshikoya KA, Van Driest SL. Clinical pharmacogenetics of cytochrome P450-associated drugs in children. J Pers Med. 2017;7:14. doi:10.3390/jpm7040014
2. Lee SHR, Yang JJ. Pharmacogenomics in acute lymphoblastic leukemia. Best Pract Res Clin Haematol. 2017;30:229–236. doi:10.1016/j.beha.2017.07.007
3. Moriyama T, Relling MV, Yang JJ. Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 2015;125:3988–3995. doi:10.1182/blood-2014-12-580001
4. Cheok MH, Pottier N, Kager L, Evans WE. Pharmacogenetics in acute lymphoblastic leukemia. Semin Hematol. 2009;46:39–51. doi:10.1053/j.seminhematol.2008.09.002
5. Lancia P, Adam de Beaumais T, Elie V, et al. Pharmacogenetics of post-transplant diabetes mellitus in children with renal transplantation treated with tacrolimus. Pediatr Nephrol. 2018;33:1045–1055. doi:10.1007/s00467-017-3881-3
6. Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics. 2008;9:1267–1284. doi:10.2217/14622416.9.9.1267
7. Wehry AM, Ramsey L, Dulemba SE, Mossman SA, Strawn JR. Pharmacogenomic testing in child and adolescent psychiatry: an evidence-based review. Curr Probl Pediatr Adolesc Health Care. 2018;48:40–49. doi:10.1016/j.cppeds.2017.12.003
8. Thummler S, Dor E, David R, et al. Pharmacoresistant severe mental health disorders in children and adolescents: functional abnormalities of cytochrome P450 2D6. Front Psychiatry. 2018;9:2. doi:10.3389/fpsyt.2018.00002
9. Myer NM, Boland JR, Faraone SV. Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry. 2018;23:1–8. doi:10.1038/mp.2017.234
10. Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010;11:407–419. doi:10.2217/pgs.10.28
11. Maruf AA, Greenslade A, Arnold PD, Bousman C. Antidepressant pharmacogenetics in children and young adults: A systematic review. J Affect Disord. 2019;254:98–108. doi:10.1016/j.jad.2019.05.025
12. Maagdenberg H, Bierings MB, van Ommen CH, et al. The pediatric acenocoumarol dosing algorithm: the children anticoagulation and pharmacogenetics study. J Thromb Haemost. 2018;16:1732–1742. doi:10.1111/jth.14211
13. Aldrich SL, Poweleit EA, Prows CA, Martin LJ, Strawn JR, Ramsey LB. Influence of CYP2C19 metabolizer status on escitalopram/citalopram tolerability and response in youth with anxiety and depressive disorders. Front Pharmacol. 2019;10:99. doi:10.3389/fphar.2019.00099
14. Koster ES, Raaijmakers JA, Koppelman GH, et al. Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort. Pharmacogenomics. 2009;10:1351–1361. doi:10.2217/pgs.09.79
15. Haga SB, Kantor A. Horizon scan of clinical laboratories offering pharmacogenetic testing. Health Aff (Millwood). 2018;37:717–723. doi:10.1377/hlthaff.2017.1564
16. Weitzel KW, Cavallari LH, Lesko LJ. Preemptive panel-based pharmacogenetic testing: the time is now. Pharm Res. 2017;34:1551–1555. doi:10.1007/s11095-017-2163-x
17. Janssens AC, Deverka PA. Useless until proven effective: the clinical utility of preemptive pharmacogenetic testing. Clin Pharmacol Ther. 2014;96:652–654. doi:10.1038/clpt.2014.186
18. Swanson HI. Drug metabolism by the host and gut microbiota: a partnership or rivalry? Drug Metab Dispos. 2015;43:1499–1504. doi:10.1124/dmd.115.065714
19. Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science. 2017;356:eaag2770. doi:10.1126/science.aag2770
20. Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14:273–287. doi:10.1038/nrmicro.2016.17
21. Bourgeois S, Jorgensen A, Zhang EJ, et al. A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome Med. 2016;8:2. doi:10.1186/s13073-015-0255-y
22. Qato DM, Alexander GC, Guadamuz JS, Lindau ST. Prescription medication use among children and adolescents in the United States. Pediatrics. 2018;142:e20181042. doi:10.1542/peds.2018-1042
23. Hales CM, Kit BK, Gu Q, Ogden CL. Trends in prescription medication use among children and adolescents-United States, 1999–2014. JAMA. 2018;319:2009–2020. doi:10.1001/jama.2018.5690
24. Elzagallaai AA, Greff M, Rieder MJ. Adverse drug reactions in children: the double-edged sword of therapeutics. Clin Pharmacol Ther. 2017;101:725–735. doi:10.1002/cpt.677
25. Cohen AL, Budnitz DS, Weidenbach KN, et al. National surveillance of emergency department visits for outpatient adverse drug events in children and adolescents. J Pediatr. 2008;152:416–421. doi:10.1016/j.jpeds.2007.07.041
26. Safer DJ. Age-grouped differences in adverse drug events from psychotropic medication. J Child Adolesc Psychopharmacol. 2011;21:299–309. doi:10.1089/cap.2010.0152
27. Fabie NAV, Pappas KB, Feldman GL. The current state of newborn screening in the United States. Pediatr Clin North Am. 2019;66:369–386. doi:10.1016/j.pcl.2018.12.007
28. Sachs HC. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132:e796–e809. doi:10.1542/peds.2013-1985
29. Colvin L, Slack-Smith L, Stanley FJ, Bower C. Pharmacovigilance in pregnancy using population-based linked datasets. Pharmacoepidemiol Drug Saf. 2009;18:211–225. doi:10.1002/pds.1705
30. Haas DM, Marsh DJ, Dang DT, et al. Prescription and other medication use in pregnancy. Obstet Gynecol. 2018;131:789–798. doi:10.1097/aog.0000000000002579
31. Berard A, Sheehy O. The quebec pregnancy cohort–prevalence of medication use during gestation and pregnancy outcomes. PLoS One. 2014;9:e93870. doi:10.1371/journal.pone.0093870
32. Daw JR, Mintzes B, Law MR, Hanley GE, Morgan SG. Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001–2006). Clin Ther. 2012;34:239–249.e232. doi:10.1016/j.clinthera.2011.11.025
33. Bakker MK, Jentink J, Vroom F, Van Den Berg PB, De Walle HE, De Jong-Van Den Berg LT. Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. Bjog. 2006;113:559–568. doi:10.1111/j.1471-0528.2006.00927.x
34. Irvine L, Flynn RW, Libby G, Crombie IK, Evans JM. Drugs dispensed in primary care during pregnancy: a record-linkage analysis in Tayside, Scotland. Drug Safely. 2010;33:593–604. doi:10.2165/11532330-000000000-00000
35. Lacroix I, Hurault C, Sarramon MF, et al. Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database. Eur J Clin Pharmacol. 2009;65:839–846. doi:10.1007/s00228-009-0647-2
36. Smolina K, Hanley GE, Mintzes B, Oberlander TF, Morgan S. Trends and determinants of prescription drug use during pregnancy and postpartum in British Columbia, 2002–2011: a population-based cohort study. PLoS One. 2015;10:e0128312. doi:10.1371/journal.pone.0128312
37. Ko JY, Patrick SW, Tong VT, Patel R, Lind JN, Barfield WD. Incidence of Neonatal Abstinence Syndrome - 28 States, 1999–2013. MMWR Morb Mortal Wkly Rep. 2016;65:799–802. doi:10.15585/mmwr.mm6531a2
38. Bailey NA, Diaz-Barbosa M. Effect of maternal substance abuse on the fetus, neonate, and child. Pediatr Rev. 2018;39:550–559. doi:10.1542/pir.2017-0201
39. Lewis T, Dinh J, Leeder JS. Genetic determinants of fetal opiate exposure and risk of neonatal abstinence syndrome: knowledge deficits and prospects for future research. Clin Pharmacol Ther. 2015;98:309–320. doi:10.1002/cpt.159
40. Nechanska B, Mravcik V, Skurtveit S, et al. Neonatal outcomes after fetal exposure to methadone and buprenorphine: national registry studies from the Czech Republic and Norway. Addiction. 2018;113:1286–1294. doi:10.1111/add.14192
41. Minozzi S, Amato L, Bellisario C, Ferri M, Davoli M. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database Syst Rev. 2013. doi:10.1002/14651858.CD006318.pub3
42. Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: a systematic review. Int Breastfeed J. 2015;10:28. doi:10.1186/s13006-015-0053-6
43. Stultz EE, Stokes JL, Shaffer ML, Paul IM, Berlin CM. Extent of medication use in breastfeeding women. Brreastfeeding Med. 2007;2:145–151. doi:10.1089/bfm.2007.0010
44. Al-Sawalha NA, Tahaineh L, Sawalha A, Almomani BA. Medication use in breastfeeding women: a national study. Breastfeeding Med. 2016;11:386–391. doi:10.1089/bfm.2016.0044
45. Spiesser-Robelet L, Brunie V, de Andrade V, Gagnayre R. Knowledge, representations, attitudes, and behaviors of women faced with taking medications while breastfeeding. J Hum Lact. 2017;33:98–114. doi:10.1177/0890334416679383
46. Haas DM, D’Alton M. Pharmacogenetics and other reasons why drugs can fail in pregnancy: higher dose or different drug? Obstet Gynecol. 2012;120:1176–1179. doi:10.1097/AOG.0b013e3182698538
47. Haas DM. Pharmacogenetics and individualizing drug treatment during pregnancy. Pharmacogenomics. 2014;15:69–78. doi:10.2217/pgs.13.228
48. Costantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016;214:
49. Eyal S, Easterling TR, Carr D, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38:833–840. doi:10.1124/dmd.109.031245
50. Feghali M, Venkataramanan R, Caritis S. Pharmacokinetics of drugs in pregnancy. Semin Perinatol. 2015;39:512–519. doi:10.1053/j.semperi.2015.08.003
51. Tasnif Y, Morado J, Hebert MF. Pregnancy-related pharmacokinetic changes. Clin Pharmacol Ther. 2016;100:53–62. doi:10.1002/cpt.382
52. Lemon LS, Zhang H, Hebert MF, et al. Ondansetron exposure changes in a pregnant woman. Pharmacotherapy. 2016;36:e139–e141. doi:10.1002/phar.1796
53. Tracy TS, Venkataramanan R, Glover DD, Caritis SN. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005;192:633–639. doi:10.1016/j.ajog.2004.08.030
54. Ryu RJ, Eyal S, Easterling TR, et al. Pharmacokinetics of metoprolol during pregnancy and lactation. J Clin Pharmacol. 2016;56:581–589. doi:10.1002/jcph.631
55. Hebert MF, Easterling TR, Kirby B, et al. Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clin Pharmacol Ther. 2008;84:248–253. doi:10.1038/clpt.2008.1
56. Taylor LG, Bird ST, Sahin L, et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017;26:592–596. doi:10.1002/pds.4185
57. Manuck TA. Pharmacogenomics of preterm birth prevention and treatment. Bjog. 2016;123:368–375. doi:10.1111/1471-0528.13744
58. Baber M, Chaudhry S, Kelly L, et al. The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics J. 2015;15:430–435. doi:10.1038/tpj.2015.3
59. Baber M, Bapat P, Nichol G, Koren G. The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review. Pharmacogenomics. 2016;17:75–93. doi:10.2217/pgs.15.157
60. VanderVaart S, Berger H, Sistonen J, et al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study. Ther Drug Monit. 2011;33:425–432. doi:10.1097/FTD.0b013e3182272b10
61. Wang J, Johnson T, Sahin L, et al. Evaluation of the safety of drugs and biological products used during lactation: workshop summary. Clin Pharmacol Ther. 2017;101:736–744. doi:10.1002/cpt.676
62. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100:42–52. doi:10.1002/cpt.377
63. Rowe H, Baker T, Hale TW. Maternal medication, drug use, and breastfeeding. Child Adolesc Psychiatr Clin N Am. 2015;24:1–20. doi:10.1016/j.chc.2014.09.005
64. Anderson PO. Drugs in Lactation. Pharm Res. 2018;35:45. doi:10.1007/s11095-017-2287-z
65. Kronenfeld N, Berlin M, Shaniv D, Berkovitch M. Use of psychotropic medications in breastfeeding women. Birth Defects Res. 2017;109:957–997. doi:10.1002/bdr2.1077
66. Anderson PO, Manoguerra AS, Valdes V. A review of adverse reactions in infants from medications in breastmilk. Clin Pediatr (Phila). 2016;55:236–244. doi:10.1177/0009922815594586
67. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95:376–382. doi:10.1038/clpt.2013.254
68. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet (London, England). 2006;368:704. doi:10.1016/S0140-6736(06)69255-6
69. Madadi P, Hildebrandt D, Gong IY, et al. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics. 2010;126:e986–e989. doi:10.1542/peds.2009-1907
70. Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther. 2009;85:31–35. doi:10.1038/clpt.2008.157
71. US Food and Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm
72. Brown JT, Abdel-Rahman SM, van Haandel L, Gaedigk A, Lin YS, Leeder JS. Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD. Clin Pharmacol Ther. 2016;99:642–650. doi:10.1002/cpt.319
73. Wagner JB, Abdel-Rahman S, Van Haandel L, et al. Impact of SLCO1B1 genotype on pediatric simvastatin acid pharmacokinetics. J Clin Pharmacol. 2018;58:823–833. doi:10.1002/jcph.1080
74. Hagos FT, Horvat CM, Au AK, et al. Factors contributing to fentanyl pharmacokinetic variability among diagnostically diverse critically ill children. Clin Pharmacokinet. 2019. doi:10.1007/s40262-019-00773-1
75. Goncalves BP, Pett H, Tiono AB, et al. Age, weight, and CYP2D6 genotype are major determinants of primaquine pharmacokinetics in African children. Antimicrob Agents Chemother. 2017;61. doi:10.1128/aac.02590-16
76. McLaughlin MJ, Wagner J, Shahknovich V, Carleton B, Leeder JS. Considerations for implementing precision therapeutics for children. Clin Transl Sci. 2019;12:140–150. doi:10.1111/cts.12607
77. Leeder JS, Meibohm B. Challenges and opportunities for increasing the knowledge base related to drug biotransformation and pharmacokinetics during growth and development. Drug Metab Dispos. 2016;44:916–923. doi:10.1124/dmd.116.071159
78. Elmorsi Y, Barber J, Rostami-Hodjegan A. Ontogeny of hepatic drug transporters and relevance to drugs used in pediatrics. Drug Metab Dispos. 2016;44:992–998. doi:10.1124/dmd.115.067801
79. Brouwer KL, Aleksunes LM, Brandys B, et al. Human ontogeny of drug transporters: review and recommendations of the pediatric transporter working group. Clin Pharmacol Ther. 2015;98:266–287. doi:10.1002/cpt.176
80. Neyro V, Jacqz-Aigrain E, Adam de Beaumais T. Pharmacogenetics and application in pediatrics. Therapie. 2018;73:157–163. doi:10.1016/j.therap.2017.11.010
81. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–1167. doi:10.1056/NEJMra035092
82. Kendrick JG, Carr RR, Ensom MH. Pediatric obesity: pharmacokinetics and implications for drug dosing. Clin Ther. 2015;37:1897–1923. doi:10.1016/j.clinthera.2015.05.495
83. Blake MJ, Abdel-Rahman SM, Pearce RE, Leeder JS, Kearns GL. Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res. 2006;60:717–723. doi:10.1203/01.pdr.0000245909.74166.00
84. Pagerols M, Richarte V, Sanchez-Mora C, et al. Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder. Pharmacogenomics J. 2016. doi:10.1038/tpj.2015.89
85. Dai D, Feinstein JA, Morrison W, Zuppa AF, Feudtner C. Epidemiology of polypharmacy and potential drug-drug interactions among pediatric patients in ICUs of U.S. children’s hospitals. Pediatr Crit Care Med. 2016;17:e218–e228. doi:10.1097/pcc.0000000000000684
86. Piekos S, Pope C, Ferrara A, Zhong XB. Impact of drug treatment at neonatal ages on variability of drug metabolism and drug-drug interactions in adult life. Curr Pharmacol Rep. 2017;3:1–9. doi:10.1007/s40495-016-0078-6
87. Neavin D, Kaddurah-Daouk R, Weinshilboum R. Pharmacometabolomics informs pharmacogenomics. Metabolomics. 2016;12. doi:10.1007/s11306-016-1066-x
88. Cohen IV, Cirulli ET, Mitchell MW, et al. Acetaminophen (Paracetamol) use modifies the sulfation of sex hormones. EBioMedicine. 2018;28:316–323. doi:10.1016/j.ebiom.2018.01.033
89. Klein ME, Parvez MM, Shin J-G. Clinical implementation of pharmacogenomics for personalized precision medicine: barriers and solutions. J Pharm Sci. 2017;106:2368–2379. doi:http://dx.doi.org/10.1016/j.xphs.2017.04.051
90. Pritchard DE, Moeckel F, Villa MS, Housman LT, McCarty CA, McLeod HL. Strategies for integrating personalized medicine into healthcare practice pers med. Per Med. 2017;14:141–152. doi:10.2217/pme-2016-0064
91. Dunnenberger HM, Crews KR, Hoffman JM, et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu Rev Pharmacol Toxicol. 2015;55:89–106. doi:10.1146/annurev-pharmtox-010814-124835
92. Cavallari LH, Lee CR, Duarte JD, et al. Implementation of inpatient models of pharmacogenetics programs. Am J Health Syst Pharm. 2016;73:1944–1954. doi:10.2146/ajhp150946
93. Sissung TM, McKeeby JW, Patel J, et al. Pharmacogenomics implementation at the national institutes of health clinical center. J Clin Pharmacol. 2017;57(Suppl 10):S67–s77. doi:10.1002/jcph.993
94. Dunnenberger HM, Biszewski M, Bell GC, et al. Implementation of a multidisciplinary pharmacogenomics clinic in a community health system. Am J Health Syst Pharm. 2016;73:1956–1966. doi:10.2146/ajhp160072
95. Huddleston KL, Klein E, Fuller A, Jo G, Lawrence G, Haga SB. Introducing personalized health for the family: the experience of a single hospital system. Pharmacogenomics. 2017;18:1589–1594. doi:10.2217/pgs-2017-0112
96. Ramsey LB, Prows CA, Zhang K, et al. Implementation of pharmacogenetics at cincinnati children’s hospital medical center: lessons learned over 14 years of personalizing medicine. Clin Pharmacol Ther. 2019;105:49–52. doi:10.1002/cpt.1165
97. Hoffman JM, Haidar CE, Wilkinson MR, et al. PG4KDS: A model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C. 2014;166:45–55. doi:10.1002/ajmg.c.31391
98. Clark MM, Hildreth A, Batalov S, et al. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. Sci Transl Med. 2019;11. doi:10.1126/scitranslmed.aat6177
99. Kuehne B, Heine E, Dafsari HS, et al. Use of whole exome sequencing in the NICU: case of an extremely low birth weight infant with syndromic features. Mol Cell Probes. 2019;45:89–93. doi:10.1016/j.mcp.2019.03.002
100. Holm IA, Agrawal PB, Ceyhan-Birsoy O, et al. The BabySeq project: implementing genomic sequencing in newborns. BMC Pediatr. 2018;18:225. doi:10.1186/s12887-018-1200-1
101. Ceyhan-Birsoy O, Machini K, Lebo MS, et al. A curated gene list for reporting results of newborn genomic sequencing. Genet Med. 2017;19:809–818. doi:10.1038/gim.2016.193
102. Botkin JR, Belmont JW, Berg JS, et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 2015;97:6–21. doi:10.1016/j.ajhg.2015.05.022
103. Ross LF, Saal HM, David KL, Anderson RR; American Academy of, P.; American College of Medical, G. Genomics. technical report: ethical and policy issues in genetic testing and screening of children. Genet Med. 2013;15:234–245. doi:10.1038/gim.2012.176
104. Committee on Bioethics. Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;107:1451–1455. doi:10.1542/peds.107.6.1451
105. Committee On Bioethics, Committee On Genetics, and, The American College Of Medical Genetics and, Genomics Social, Ethical, and Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Pediatrics. 2013;131:620–622. doi:10.1542/peds.2012-3680
106. Wilfond B, Ross LF. From genetics to genomics: ethics, policy, and parental decision-making. J Pediatr Psychol. 2009;34:639–647. doi:10.1093/jpepsy/jsn075
107. Wilfond BS, Pelias MZ, Knoppers BM, et al. Points to consider - ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 1995;57:1233–1241.
108. Pelias MK. Genetic testing of children for adult-onset diseases: is testing in the child’s best interests? Mt Sinai J Med. 2006;73:605–608.
109. Robertson S, Savulescu J. Is there a case in favour of predictive genetic testing in young children? Bioethics. 2001;15:26–49.
110. Malpas PJ. Predictive genetic testing of children for adult-onset diseases and psychological harm. J Med Ethics. 2008;34:275–278. doi:10.1136/jme.2006.019802
111. Wu YP, Mays D, Kohlmann W, Tercyak KP. Pediatric predispositional genetic risk communication: potential utility for prevention and control of melanoma risk as an exemplar. J Genet Couns. 2017;26:887–893. doi:10.1007/s10897-017-0105-8
112. Schiavone S, Neri M, Pomara C, Riezzo I, Trabace L, Turillazzi E. Personalized medicine in the paediatric population: the balance between pharmacogenetic progress and bioethics. Curr Pharm Biotechnol. 2017;18:253–262. doi:10.2174/1389201018666170207130236
113. Deem MJ. Whole-genome sequencing and disability in the NICU: exploring practical and ethical challenges. Pediatrics. 2016;137(Suppl 1):S47–S55. doi:10.1542/peds.2015-3731I
114. Sing CW, Cheung CL, Wong IC. Pharmacogenomics–how close/far are we to practising individualized medicine for children? Br J Clin Pharmacol. 2015;79:419–428. doi:10.1111/bcp.12338
115. Committee On Bioethics; Committee On Genetics; American College Of Medical Genetics and Genomics Social Ethical Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Pediatrics. 2013;131:620–622. doi:10.1542/peds.2012-3680
116. Haga SB, O’Daniel JM, Tindall GM, Lipkus IR, Agans R. Survey of US public attitudes toward pharmacogenetic testing. Pharmacogenomics J. 2012;12:197–204. doi:10.1038/tpj.2011.1
117. Daud ANA, Bergsma EL, Bergman JEH, et al. Knowledge and attitude regarding pharmacogenetics among formerly pregnant women in the Netherlands and their interest in pharmacogenetic research. BMC Pregnancy Childbirth. 2017;17:120. doi:10.1186/s12884-017-1290-z
118. Lee YM, Manzoor BS, Cavallari LH, Nutescu EA. Facilitators and barriers to the adoption of pharmacogenetic testing in an inner-city population. Pharmacotherapy. 2018;38:205–216. doi:10.1002/phar.2077
119. Poweleit EA, Aldrich SL, Martin LJ, Hahn D, Strawn JR, Ramsey LB. Pharmacogenetics of sertraline tolerability and response in pediatric anxiety and depressive disorders. J Child Adolesc Psychopharmacol. 2019;29:348–361. doi:10.1089/cap.2019.0017
120. Allegra S, Fatiguso G, Francia S, et al. Pharmacogenetic of voriconazole antifungal agent in pediatric patients. Pharmacogenomics. 2018;19:913–925. doi:10.2217/pgs-2017-0173
121. Hegyi M, Arany A, Semsei AF, et al. Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma. Oncotarget. 2017;8:9388–9398. doi:10.18632/oncotarget.11543
122. Manworren RC, Jeffries L, Pantaleao A, Seip R, Zempsky WT, Ruano G. Pharmacogenetic testing for analgesic adverse effects: pediatric case series. Clin J Pain. 2016;32:109–115. doi:10.1097/ajp.0000000000000236
123. Allegra S, De Francia S, Cusato J, et al. Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients. Pharmacogenomics. 2017;18:539–554. doi:10.2217/pgs-2016-0176
124. FDA. Table of pharmacogenomic biomarkers in drug labels. 2014. Available from: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm.
125. Green DJ, Mummaneni P, Kim IW, Oh JM, Pacanowski M, Burckart GJ. Pharmacogenomic information in FDA-approved drug labels: application to pediatric patients. Clin Pharmacol Ther. 2016;99:622–632. doi:10.1002/cpt.330
126. Leeder JS, Kearns GL. Interpreting pharmacogenetic data in the developing neonate: the challenge of hitting a moving target. Clin Pharmacol Ther. 2012;92:434–436. doi:10.1038/clpt.2012.130
127. Need AC, Goldstein DB. Next generation disparities in human genomics: concerns and remedies. Trends Genet. 2009;25:489–494. doi:10.1016/j.tig.2009.09.012
128. Aminkeng F, Ross CJ, Rassekh SR, et al. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. Pharmacogenomics J. 2014;14:160–170. doi:10.1038/tpj.2013.13
129. Mak M, Lam C, Pineda SJ, et al. Pharmacogenetics of warfarin in a diverse patient population. J Cardiovasc Pharmacol Ther. 2019;24:521–533. doi:10.1177/1074248419843530
130. Corvol H, De Giacomo A, Eng C, et al. Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma. Pharmacogenet Genomics. 2009;19:489–496. doi:10.1097/FPC.0b013e32832c440e
131. McGrane IR, Loveland JG. Pharmacogenetics of cytochrome P450 enzymes in American Indian and Caucasian Children Admitted to a Psychiatric Hospital. J Child Adolesc Psychopharmacol. 2016;26:395–399. doi:10.1089/cap.2015.0180
132. Henderson LM, Claw KG, Woodahl EL, et al. P450 Pharmacogenetics in indigenous North American populations. J Pers Med. 2018;8:9. doi:10.3390/jpm8010009
133. Naranjo MG, Rodrigues-Soares F, Penas-Lledo EM, et al. Interethnic variability in CYP2D6, CYP2C9, and CYP2C19 genes and predicted drug metabolism phenotypes among 6060 Ibero- and Native Americans: RIBEF-CEIBA consortium report on population pharmacogenomics. Omics. 2018;22:575–588. doi:10.1089/omi.2018.0114
134. Renga B. Non invasive prenatal diagnosis of fetal aneuploidy using cell free fetal DNA. Eur J Obstet Gynecol Reprod Biol. 2018;225:5–8. doi:10.1016/j.ejogrb.2018.03.033
135. Kuhlmann-Capek M, Chiossi G, Singh P, et al. Effects of medication intake in early pregnancy on the fetal fraction of cell-free DNA testing. Prenat Diagn. 2019;39:361–368. doi:10.1002/pd.5436
136. Frankel LA, Pereira S, McGuire AL. Potential psychosocial risks of sequencing newborns. Pediatrics. 2016;137(Suppl 1):S24–S29. doi:10.1542/peds.2015-3731F
137. de Oliveira FF, Chen ES, Smith MC, Bertolucci PHF. Pharmacogenetics of angiotensin-converting enzyme inhibitors in patients with Alzheimer’s disease dementia. Curr Alzheimer Res. 2018;15:386–398. doi:10.2174/1567205014666171016101816
138. Berkowitz CL, Mosconi L, Rahman A, Scheyer O, Hristov H, Isaacson RS. Clinical application of APOE in Alzheimer’s prevention: a precision medicine approach. J Prev Alzheimers Dis. 2018;5:245–252. doi:10.14283/jpad.2018.35
139. Haga SB, Mills R. A review of consent practices and perspectives for pharmacogenetic testing. Pharmacogenomics. 2016;17:1595–1605. doi:10.2217/pgs-2016-0039
140. Clayton EW. How much control do children and adolescents have over genomic testing, parental access to their results, and parental communication of those results to others? J Law Med Ethics. 2015;43:538–544. doi:10.1111/jlme.12296
141. Mills R. Development and initial assessment of a patient education video about pharmacogenetics. J Pers Med. 2017;7. doi:10.3390/jpm7020004
142. Lewis MA, Paquin RS, Roche MI, et al. Supporting parental decisions about genomic sequencing for newborn screening: the NC NEXUS decision aid. Pediatrics. 2016;137(Suppl 1):S16–S23. doi:10.1542/peds.2015-3731E
143. Amara N, Blouin-Bougie J, Bouthillier D, Simard J. On the readiness of physicians for pharmacogenomics testing: an empirical assessment. Pharmacogenomics J. 2018;18:308–318. doi:10.1038/tpj.2017.22
144. Weitzel KW, Aquilante CL, Johnson S, Kisor DF, Empey PE. Educational strategies to enable expansion of pharmacogenomics-based care. Am J Health Syst Pharm. 2016;73:1986–1998. doi:10.2146/ajhp160104
145. Giri J, Curry TB, Formea CM, Nicholson WT, Rohrer Vitek CR. Education and knowledge in pharmacogenomics: still a challenge? Clin Pharmacol Ther. 2018;103:752–755. doi:10.1002/cpt.1019
146. Haga SB. Primary care physicians’ knowledge of and experience with pharmacogenetic testing. Pharmgenomics Pers Med. 2012;82:388–394. doi:10.1111/j.1399-0004.2012.01908.x.
147. Katsanis SH, Minear MA, Vorderstrasse A, et al. Perspectives on genetic and genomic technologies in an academic medical center: the duke experience. J Pers Med. 2015;5:67–82. doi:10.3390/jpm5020067
148. Hinderer M, Boeker M, Wagner SA, et al. The experience of physicians in pharmacogenomic clinical decision support within eight German university hospitals. Pharmacogenomics. 2017;18:773–785. doi:10.2217/pgs-2017-0027
149. Owusu Obeng A, Fei K, Levy KD, et al. Physician-reported benefits and barriers to clinical implementation of genomic medicine: a multi-site IGNITE-network survey. J Pers Med. 2018;8:24. doi:10.3390/jpm8030024
150. Selkirk CG, Weissman SM, Anderson A, Hulick PJ. Physicians’ preparedness for integration of genomic and pharmacogenetic testing into practice within a major healthcare system. Genet Test Mol Biomarkers. 2013;17:219–225. doi:10.1089/gtmb.2012.0165
151. Green JS, O’Brien TJ, Chiappinelli VA, Harralson AF. Pharmacogenomics instruction in US and Canadian medical schools: implications for personalized medicine. Pharmacogenomics. 2010;11:1331–1340. doi:10.2217/pgs.10.122
152. Nickola TJ, Green JS, Harralson AF, O’Brien TJ. The current and future state of pharmacogenomics medical education in the USA. Pharmacogenomics. 2012;13:1419–1425. doi:10.2217/pgs.12.113
153. Higgs JE, Andrews J, Gurwitz D, Payne K, Newman W. Pharmacogenetics education in British medical schools. Genomic Med. 2008;2:101–105. doi:10.1007/s11568-009-9032-6
154. Heale BSE, Khalifa A, Stone BL, Nelson S, Del Fiol G. Physicians’ pharmacogenomics information needs and seeking behavior: a study with case vignettes. BMC Med Inform Decis Mak. 2017;17:113. doi:10.1186/s12911-017-0510-9
155. Edelman EA, Tanner PC, Taber KA, et al. Provider engagement in precision oncology education: an exploratory analysis of online continuing medical education data. Per Med. 2019;16:199–209. doi:10.2217/pme-2018-0150
156. Houwink EJ, Van Teeffelen SR, Muijtjens AM, et al. Sustained educational effect after online training in oncogenetics: a randomized controlled trial. Eur J Hum Genet. 2014;22:310–316. doi:10.1038/ejhg.2013.163
157. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Twist GP, Klein TE, Miller NA. The Evolution of PharmVar. Clin Pharmacol Ther. 2019;105:29–32. doi:10.1002/cpt.1275
158. Hoffman JM, Dunnenberger HM, Kevin Hicks J, et al. Developing knowledge resources to support precision medicine: principles from the Clinical Pharmacogenetics Implementation Consortium (CPIC). J Am Med Inform Assoc. 2016;23:796–801. doi:10.1093/jamia/ocw027
159. Barbarino JM, Whirl-Carrillo M, Altman RB, Klein TE. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018;10:e1417. doi:10.1002/wsbm.1417
160. Caudle KE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Relling MV, Klein TE. Evidence and resources to implement pharmacogenetic knowledge for precision medicine. Am J Health Syst Pharm. 2016;73:1977–1985. doi:10.2146/ajhp150977
161. Perry CG, Maloney KA, Beitelshees AL, et al. Educational innovations in clinical pharmacogenomics. Clin Pharmacol Ther. 2016;99:582–584. doi:10.1002/cpt.352
162. van der Wouden CH, Bank PCD, Ozokcu K, Swen JJ, Guchelaar HJ. Pharmacist-initiated pre-emptive pharmacogenetic panel testing with clinical decision support in primary care: record of PGx results and real-world impact. Genes. 2019;10:416. doi:10.3390/genes10060416
163. Goldspiel BR, Flegel WA, DiPatrizio G, et al. Integrating pharmacogenetic information and clinical decision support into the electronic health record. J Am Med Inform Assoc. 2014;21:522–528. doi:10.1136/amiajnl-2013-001873
164. Hicks JK, Stowe D, Willner MA, et al. Implementation of clinical pharmacogenomics within a large health system: from electronic health record decision support to consultation services. Pharmacotherapy. 2016;36:940–948. doi:10.1002/phar.1786
165. Bell GC, Crews KR, Wilkinson MR, et al. Development and use of active clinical decision support for preemptive pharmacogenomics. J Am Med Inform Assoc. 2014;21:e93–e99. doi:10.1136/amiajnl-2013-001993
166. Hicks JK, Crews KR, Hoffman JM, et al. A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record. Clin Pharmacol Ther. 2012;92:563–566. doi:10.1038/clpt.2012.140
167. Haga SB. Educating patients and providers through comprehensive pharmacogenetic test reports. Pharmacogenomics. 2017;18:1047–1050. doi:10.2217/pgs-2017-0088
168. Haga SB. Nurses’ communication of pharmacogenetic test results as part of discharge care. Clin Chem. 2015;16:251–256. doi:10.2217/pgs.14.173.
169. Daack-Hirsch S, Jackson B, Belchez CA, et al. Integrating genetics and genomics into nursing curricula: you can do it too! Nurs Clin North Am. 2013;48:661–669. doi:10.1016/j.cnur.2013.08.005
170. Jenkins JF, Calzone K. Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators.
171. Lee KC, Hudmon KS, Ma JD, Kuo GM. Evaluation of a shared pharmacogenomics curriculum for pharmacy students. Pharmacogenomics. 2015;16:315–322. doi:10.2217/pgs.14.181
172. Brown JT, Gregornik D, Kennedy MJ. The role of the pediatric pharmacist in precision medicine and clinical pharmacogenomics for children. J Pediatr Pharmacol Ther. 2018;23:499–501. doi:10.5863/1551-6776-23.6.499
173. Crews KR, Cross SJ, McCormick JN, et al. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm. 2011;68:143–150. doi:10.2146/ajhp100113
174. Zierhut HA, Campbell CA, Mitchell AG, Lemke AA, Mills R, Bishop JR. Collaborative counseling considerations for pharmacogenomic tests. Pharmacotherapy. 2017;37:990–999. doi:10.1002/phar.1980
175. Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19:215–223. doi:10.1038/gim.2016.87
176. Kalman LV, Agundez J, Appell ML, et al. Pharmacogenetic allele nomenclature: international workgroup recommendations for test result reporting. Clin Pharmacol Ther. 2016;99:172–185. doi:10.1002/cpt.280
177. Mulugeta YL, Zajicek A, Barrett J, et al. Development of drug therapies for newborns and children: the scientific and regulatory imperatives. Pediatr Clin North Am. 2017;64:1185–1196. doi:10.1016/j.pcl.2017.08.015
178. Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van Den Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211:
179. Genzen JR, Mohlman JS, Lynch JL, Squires MW, Weiss RL. Laboratory-Developed Tests: A Legislative and Regulatory Review. Clin Chem. 2017;63:1575–1584. doi:10.1373/clinchem.2017.275164
180. U.S. Food and Drug Administration. FDA authorizes first direct-to-consumer test for detecting genetic variants that may be associated with medication metabolism. Available from: https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-direct-consumer-test-detecting-genetic-variants-may-be-associated-medication.
181. Lu M, Lewis CM, Traylor M. Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe. BMC Med Genomics. 2017;10:47. doi:10.1186/s12920-017-0283-0
182. U.S. Food and Drug Administration. The FDA warns against the use of many genetic tests with unapproved claims to predict patient response to specific medications: FDA safety communication. Available from: https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific
183. U.S. Food and Drug Administration. Warning Letter – inova Genomics Laboratory. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/inova-genomics-laboratory-577422-04042019.
184. Pezalla EJ. Payer view of personalized medicine. Am J Health Syst Pharm. 2016;73:2007–2012. doi:10.2146/ajhp160038
185. Dionne F, Aminkeng F, Bhavsar AP, et al. An initial health economic evaluation of pharmacogenomic testing in patients treated for childhood cancer with anthracyclines. Pediatr Blood Cancer. 2018;65:e26887. doi:10.1002/pbc.26887
186. Moretti ME, Lato DF, Berger H, Koren G, Ito S, Ungar WJ. A cost-effectiveness analysis of maternal CYP2D6 genetic testing to guide treatment for postpartum pain and avert infant adverse events. Pharmacogenomics J. 2018;18:391–397. doi:10.1038/tpj.2017.33
187. Keeling NJ, Rosenthal MM, West-Strum D, Patel AS, Haidar CE, Hoffman JM. Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers. Genet Med. 2019;21:1224–1232. doi:10.1038/gim.2017.181
188. Dong D, Ozdemir S, Mong Bee Y, Toh SA, Bilger M, Finkelstein E. Measuring high-risk patients’ preferences for pharmacogenetic testing to reduce severe adverse drug reaction: a discrete choice experiment. Value Health. 2016;19:767–775. doi:10.1016/j.jval.2016.03.1837
189. Najafzadeh M, Johnston KM, Peacock SJ, et al. Genomic testing to determine drug response: measuring preferences of the public and patients using Discrete Choice Experiment (DCE). BMC Health Serv Res. 2013;13:454. doi:10.1186/1472-6963-13-454
190. Herbild L, Gyrd-Hansen D, Bech M. Patient preferences for pharmacogenetic screening in depression. Int J Technol Assess Health Care. 2008;24:96–103. doi:10.1017/S0266462307080129
© 2019 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.
By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.