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Genetics and Newborn Screening

January 23, 2017

John D. Thompson, PhD , MPH, MPA

Washington State Department of Health

The Case for Genetics

Neurodevelopmental Disorders • Intellectual disability

• Autism spectrum disorders

• Fetal alcohol syndrome

• Motor disorders

• Traumatic brain injury

• Communication, speech and language disorders

• Genetic disorders

• Attention deficit hyperactivity disorder

• Schizophrenia

The Case for Genetics

Case Study: Phenylketonuria (PKU)

Bob Guthrie: Father of NBS

Phenylketonuria: Simple Idea

• Screen all infants

• Remove phenylalanine from the diet

• Prevent intellectual disability, improve outcomes

Phenylketonuria: Complex Reality

• Overtreatment – malnourished

• Variable expression

• Screening test casts a wide net: – Hyperphenylalaninemia - benign – Tetrahydrobiopterin defect (1% of cases)

• Maternal PKU

Phenylketonuria: Complex Reality

• Very large numbers of patients - clinical care capacity for affected individuals (UW PKU clinic at CHDD)

• Transition into adulthood

• Language and Cultural Barriers – need interpreters and case managers

• Treatment – special medical formula – who pays?

Public Health Genetics: Newborn Screening

What is Newborn Screening?

An integrated system that includes:

• Universal screening - all infants

• Follow-up to assure appropriate clinical response

• Referral for diagnosis of affected infants

• Appropriate treatment and clinical care

• Evaluation of system effectiveness (long-term follow-up)

NBS Follow-up Systems Map

Beth Ogata quote

Case Study: Congenital Hypothyroidism

Why is Newborn Screening Important?

It prevents death and disability to affected infants by providing early treatment

It benefits the public through savings in health care and disability support costs

Two 6 year old girls with congenital hypothyroidism

1st NBS Collection (1d)

Patient Demographics

• Sex: male

• DOB: 02/04/1998 @ 0535

• Race: white

• Birth order: single

• Birthweight: 3149g (6lbs 15oz)

• Gestation: 36 weeks

• Birth hospital: Overlake

Neonatal Exam (5d)

• Clinical Symptoms:

– Constipation (less than 1 stool/day)

– Poor Feeding

Newborn Screen Results (8d)

• Date reported: 2/12/1998

• Results:

– T4 = 7.4 μg/dL (normal > 10)

– TSH = 454.1 μIU/mL (normal < 29.4)

Reporting NBS Results (8d)

• Contacted provider

– Follow-up staff reported results to PCP

– Instructions: • Obtain blood for serum thyroid studies

• Perform thyroid scan

• Consult with Pediatric Endocrinologist

• Submit a routine 2nd NBS

• Official report mailed

• Follow-up on infant’s status

Treatment Started (12d)

• Intervention

– Medication: Levothyroxine

(synthetic thyroid hormone)

Newborn Thyroid Clinical Evaluation

(16d)

• Seen by Pediatric Endocrinologist

• 1st Exam since notification of abnormal NBS

• No family history of thyroid disorders

• Mother was not exposed to iodine or antithyroid drugs during pregnancy

• Technetium scan completed at Seattle Children’s

• Infant weight 7 lbs. 4 oz. (5 oz. gained since birth)

• No physical or neurological development problems

• Treatment: Continue Levothyroxine

Referral to UW CH Clinic 1 month – 4 years old

03/10/1998 Letter sent to parents by NBS Coordinator enquiring if

parents would like to enroll Aiden with the Congenital

Hypothyroidism Developmental Evaluation Clinic

at the University of Washington.

06/15/1998 Signed Parental Consent Form Received

06/19/1998 NBS Program sends parent information to Clinic

Coordinator at UW

07/31/1998 1st Clinic Visit

02/19/1999 2nd Clinic Visit

08/18/2000 3rd Clinic Visit

04/05/2002 4th Clinic Visit

Fast Forward - 2015

• Telephone call

– High school senior

– Hypothyroidism

– Science project

• Tour of NBS lab

• Q&A during school

year

Aiden Today

• Science expo

award winner:

education

• UW student

– Pre-med

– Rowing team

– Research interests

in NBS

Annual Newborn Screening Numbers

Screen ~85,000 newborns

Receive ~170,000 specimens

Track ~5,000 infants with abnormal results

Prevent ~200 babies from death or disability

Annual Newborn Screening Numbers

Screen ~85,000 newborns

Prevent ~200 babies from death or disability

NBS Sequence of Events

recommended window for NBS specimen collection

hospital – blood collection

transit time

NBS lab testing

follow-up

Birth 1 Time (days)

2 3 4 5 6 7

Washington Criteria for NBS

Early identification benefits the newborn

Treatment is available

Nature of the condition justifies population-based screening

A good screening test exists

The benefits justify the costs of screening

PKU CH CAH HB

2003 2006

PKU CH CAH HB BIO GALT MCADD MSUD HCYS CF

2008

PKU CH CAH HB BIO GALT MCADD MSUD HCYS CF

2010 PKU CH CAH Hb Bio GALT MCADD MSUD HCYS CF ASA CIT TYR-I GA-I IVA MMA PROP HMG BKT MCD VLCADD LCHADD TFP CUD

Case Study #3

Improving the Sensitivity of the Screen for Cystic Fibrosis

PKU CH CAH Hb Bio GALT MCADD MSUD HCYS CF ASA CIT TYR-I GA-I IVA MMA PROP HMG BKT MCD VLCADD LCHADD TFP CUD SCID

2014

Level of Urgency

HIGH!! • CAH

• Galactosemia

• MSUD

• CIT/ASA

• VLCAD/LCHAD/TFP

• IVA

• MMA/PROP

• CCHD

Diagnosis and treatment should be initiated ASAP!

Level of Urgency

MODERATE

• Biotinidase deficiency

• Congenital Hypothyroidism

• Homocystinuria

• MCAD

• PKU

• GA-I

• BKT

Treatment recommended by 1 to 3 weeks of age

Level of Urgency

Low – can wait over a weekend to contact baby’s provider

• Cystic Fibrosis

• Hemoglobin disorders

• TYR-I

• HMG/MCD

• CUD

• Hearing Loss

• SCID

Treatment recommended by 3 to 4 weeks of age

How is screening done?

Specimen Testing – A variety of testing platforms are used to screen for the 28 disorders

– Any abnormal result is repeated in duplicate for confirmation

Washington State Department of Health

Hemoglobin Gel Electrophoresis 3 disorders 1 punch

Flouroimmunoassay Instrument 3 disorders 3 punches

PCR Instrument 1 disorder

1 punch

Tandem Mass Spectrometer 19 disorders 1 punch

Spectrophotometer 2 disorders 2 punches

Current Events – NBS Expansion

“I have come to the conclusion that the making of laws is like the making of

sausages – the less you know about the process the more you respect the result.”

- Frank W. Tracy quoting an unnamed member of the Illinois House of Representatives (about 1878)

Rule Making Process

Revised Code of Washington

• Compilation of all permanent laws/statutes now in force (Statutory Law)

• Authorizes the development of Administrative Law (WAC)

Revised Code of Washington

• Title 70 – Public Health and Safety

– Chapter 70.83 – Phenylketonuria and other preventable heritable disorders

• Section 010 – Declaration of policy and purpose

• Section 020 – Screening tests of newborn infants

• Section 050 – Rules and regulations (SBOH)

also

• Chapter 70.02 – Medical records – Health care information access and disclosure

Washington Administrative Code

• Rules or Regulations of executive branch agencies (Administrative Law)

– Written requirements

– Apply broadly to groups or entities

– Enable, guide or direct/prohibit

(basically, it’s how we run our program)

• Title 246 – Department of Health

– Chapter 650 – Newborn Screening

• Section 001 – Purpose

• Section 020 – Performance of screening tests – Hospital procedures

– Conditions on screening panel

• Section 040 – Report to the board

• Section 050 – Privacy and security

• Section 990 – Screening charge

Washington Administrative Code

So, how do we change the law?

ALD timeline • 2014 – Parent advocate request

– SBOH to consider adding ALD

• 2015 – NBS advisory committee review

– Recommended for RUSP

• 2016 – DOH decision package

– CR101 filed

• 2017 – Legislative process to increase NBS fee

– NBS laboratory expansion

• 2018 – Start screening babies for ALD

Current Events - Cutoffs

Laboratory Testing

Normal Cases

Normal Cases

Distribution of lab values

Ideal

Common

Laboratory Testing

Normal Cases

Distribution of lab values

False (+) False (-)

Laboratory Testing

Ways to mitigate false results:

• Stratify results • birthweight • age at collection • secondary analytes or ratios

• Routine 2nd screens • Collaborative NBS data repositories

End goal – reduce the impact on families

Newborn Screening System

• Contracts with specialty care facilities • Help establish diagnoses – weekly

conference calls for pending cases • Meet with newly diagnosed patients –

educate families • Provide long-term support/follow-up to

ensure healthy outcomes • Quality improvement initiatives

– Screening – Clinical care

• Moral support

NBS – Clinical Partnership

Washington State

Newborn Screening

www.doh.wa.gov/nbs

(206) 418-5410

or

1-866-660-9050