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Screening Newborns for Late Onset Disorders: Should We, or Shouldn’t We?

Melissa Wasserstein, MD

Chief, Division of Pediatric Genetic Medicine

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Disclosure InformationMelissa Wasserstein, MD

I have the following financial relationships to disclose:

Consultant for: Sanofi Genzyme

Grant/Research support from: Sanofi Genzyme

I will not discuss off label use and/or investigational use in my presentation.

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And a disclaimer….

I’m not an ethicist

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“Your scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”

Ian Malcolm, 1993

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There are compelling reasons to screen newborns for LSDs, X-ALD, Krabbe

• In general, these are serious diseases with significant morbidity and mortality

• There are low cost, high throughput DBS assays

• There are treatments

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But they all have broad phenotypic spectra, including later onset subtypes

Disease Infantile Onset Childhood Onset Adult Onset

Krabbe Disease Classic Later Onset

X-ALD CCALD AMN, Adult cerebral, etc.

MPS1 Severe Attenuated

Pompe Classic Juvenile Adult Onset

Gaucher Type 2 Type 3, Type 1 Type 1

Fabry Type 1 Type 2

ASMD Niemann Pick A Niemann Pick B

Predominant phenotype

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General features of later onset LSDs and XALD

• Variability

– Some individuals may have serious disease, but some may be so mild as to go undiagnosed and not require treatment

– They have variable ages at presentation ranging from early childhood to the eighth decade of life

– It is currently very difficult (if not impossible) to predict disease severity via a DBS assay

• Treatment

– ERT/SRT is available for Fabry, Gaucher, MPS1, Pompe

– Treatment options for Krabbe and non-CCALD XALD are less clear cut

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NBS for these later onset disorders is currently live or mandated in several states

Krabbe Pompe Fabry Gaucher MPS1 ASMD X-ALD

NY x x x x x x x

NJ x x x x x x x

CA x

IL x x x x x x x

MO x x x x x x

CT x

MD x

PA x x x x x x x

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Newborn screening is for babies!

• Traditionally, the moral focus of newborn screening has been “what is good for the infant.”

• The underlying implication is that there should be a direct medical benefit to the infant through early diagnosis and treatment

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• In the past, most professional medical societies took a firm stand against predictive genetic testing in children for adult onset conditions

– Risks of

• The “vulnerable child”

• Loss of autonomy

• Psychological stresses associated with being a “patient in waiting”

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• There is increasing pressure to screen for a wider array of disorders, many of which are later onset.

– This includes specific diseases, as well as broader genomic testing of newborns

• The concept against screening newborns for “non-baby” diseases requires reconsideration.

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What guidelines do we use to determine whether or not we should screen newborns for later onset diseases?

Do “traditional” newborn screening guidelines still pertain?

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Principles of Screening:Wilson and Jungner Criteria

• The condition sought should be an important health problem.

• There should be an accepted treatment for patients with recognized disease.

• Facilities for diagnosis and treatment should be available.

• There should be a recognizable latent or early symptomatic stage.

• There should be a suitable test or examination.

• The test should be acceptable to the population.

• The natural history of the condition, including development from latent to declared disease, should be adequately understood.

• There should be an agreed policy on whom to treat as patients.

• The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.

• Case-finding should be a continuing process and not a “once and for all” project.

• James M. G. Wilson and Gunnar Jungner, Principles and Practice of Screening for Disease (Geneva: World Health Organization, 1968), available online at whqlib- doc.who.int/php/WHO_PHP_34.pdf.

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What else?

• More recent professional society statements generally conclude: “Data is necessary to assess potential positive and negative effects of genetic testing in childhood.”

• Data is needed

– What are the benefits?

– What are the risks?

– Is it feasible and practical?

– Is it cost-effective?

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Benefits of NBS for early onset diseases: Individual

• Earlier access to treatment

– This is expected to result in a better outcome

• Prevents diagnostic odyssey

• Knowledge about diagnosis permits an individual (or a parent) to make informed decisions

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Benefits of NBS for early onset diseases: Beyond the individual

• Benefits to the family

– Family planning

– Testing at risk family members

• Benefits to society

– Collecting data to inform the medical community about the natural history, phenotypic spectrum, treatment options, etc.

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But… with later onset conditions, these benefits are not as clear-cut

• Re-evaluation of benefits to the individual

– Earlier access to treatment

• This is expected to result in a better outcome

• Moreover..– If an individual has a mild phenotype that does not require

treatment, this is not a benefit

– There may be a risk of overtreatment (too early, or unnecessarily), with inherent risks and expense

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Re-evaluation of benefits to the individual in later onset diseases

• Prevents diagnostic odyssey

– Probably, but there may be a risk of having unrelated signs/symptoms automatically ascribed to the known disease

• Knowledge about diagnosis permits an individual to make informed decisions about one’s health and other important decisions

– Might this negatively impact decision making? (Choosing not to go to college, get married, have

children, etc.)

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Potential harms of Newborn Screening for early onset diseases

• Harms associated with overtreatment

– Ex. Over-restriction of phenylalanine prior to recognition of benign hyperphenylalaninemia

• Psychological harms associated with false positives

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Potential harms associated with screening newborns for later onset conditions

• Harms associated with overtreatment

• Psychological harms associated with false positives

• Psychological harms associated with knowing about a future illness

– Vulnerable child syndrome

– Stresses associated with the “unbearable certainty of knowing” that disease is inevitable

– Stresses associated with uncertainty of knowing if/when/how disease might occur

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Potential harms related to insurability

• Affordable Care Act: People with pre-existing conditions can’t be denied coverage or charged more for coverage than healthy people (exception of smoking)

• Current Trumpcare Proposal: Insurers may increase premiums for people with pre-existing conditions

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Perception vs reality

• How real are these potential harms?

– Affective forecasting:

• We tend to try to predict our reaction to future emotional events

– Impact bias

• Our predictions tend to overestimate negativity

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We also need data about the practicality of screening newborns for later onset diseases

• NBS obligates access to care

• How do we maintain that obligation over decades?

– What is someone is asymptomatic and doesn’t want to come?

– Who bears responsibility for ensuring that families remember the diagnosis, and inform patients when they are adults?

– There may be medicolegal implications, but this is uncharted territory

• NY’s experience with late onset Krabbe disease suggests that there will be a high rate of “lost to follow up”

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The Lysosomal Storage Disorders: A Pilot Newborn Screen and Examination of the Associated Ethical, Legal and Social Issues

• Funded by NICHD

• Multi-Program Collaboration• Albert Einstein College of Medicine

• New York State Newborn Screening Program

• High birth rate, ethnically diverse NYC HospitalsElmhurst, Maimonides, Mount Sinai, NYU, Weiler

• Newborn Screening Translational Research Network

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Overall Goals of the Pilot NBS

• What is the accuracy of NBS for the LSDs?

• What is the overall disease incidence in an ethnically diverse population?

• What are the incidences of early vs later onset phenotypes?

• What are the risks and benefits of early diagnosis through NBS?

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Original plan to evaluate risks and benefits of NBS for later onset conditions

• Initiate process with series of guided qualitatitive interviews to learn from the parents how they perceived risks and benefits

• Data extraction to identify thematic saturation

• Series of questionnaires, some validated, some from our qualitative research

• BUT…of the first 20 true positive babies – 45% were non-English speaking

– 55% were English speakers

• But 2/3 of these were from the same deeply religious, ethno/politico/culturally similar community

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NYC Pilot NBS ELSI Survey• 10-15 minute, anonymous, online multilingual Qualtrics survey

• Overarching goal is to evaluate risks and benefits of NBS for LSDs

• Risks: Anxiety, depression, stress (validated surveys)

• Benefits: Earlier treatment, reproductive counseling, identification of at risk relatives

• Population

– Parents of infants diagnosed through NBS with:

• Later onset LSDs and X-ALD

• Early onset LSDs and X-ALD

– Parents of infants with a:

• Normal NBS

• Positive NBS for other disorders

• “Go-Live” Summer 2017

• We’ll be bugging you…..

NY, IL, MO, MD, CA, NJ

Any state

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In Conclusion

• Many newborn screening programs now include conditions with predominantly later onset phenotypes.

• Maintaining long term follow up is likely to be challenging, so practical guidelines should be established to assist clinicians with this task.

• The benefits and harms of screening newborns for later onset conditions may be different than for traditional NBS disorders, and require definitions of what, how serious, and how enduring.

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Acknowledgements Children’s Hospital at Montefiore/Albert Einstein College of MedicineBronx, NY

Nicole Kelly, BA, MPH, Project ManagerKatie Gallagher, MS, CGCJessica Fischetti, MS

Mount Sinai Medical CenterNew York, NY

Manisha Balwani, MDRobert J. Desnick, MD, PhDLissette Estrella, NPKurt Hirschhorn, MDIan Holzman, MDAlex Kenigsberg, BA, MSTRuth Kornreich, PhDDalia Makarem, MPHRosamond Rhodes, PhDSaskia Sanderson, PhDEd Schuchman, PhDAmy Yang, MDChunli Yu, MDJinglan Zhang, PhD

Newborn Screening Translational NetworkAmy Brower, PhDJen LoutrelMike Watson PhD

Duke University Medical CenterNorth Carolina

Priya Kishnani, MDDeeksha Bali, PhD

New York State Department of Health: Newborn Screening LaboratoryAlbany, NY

Joseph Orsini, PhDMichele Caggana, ScDBeth Vogel, MS, GCRyan WilsonChad BiskiChristopher JohnsonMonica Martin

Elmhurst Medical CenterQueens, NY

Randi Wasserman, MDDalia Makarem, MPH

Maimonides Medical CenterBrooklyn, NY

Gabriel Kupchik, MDTori Velez

New York University Medical CenterNew York, NY

Sean Bailey MDKatherine CaromeRebecca Zarchin

Weiler HospitalBronx, NY

Aliza QuinonesSuhas Nafday, MDDeborah Campbell, MD

The Pilot NBS is supported by the Eunice Kennedy Shriver NICHD of the NIH under Award Number 5R01HD073292-05