This Podcast Will Kill You

Ep 189 Newborn screening: The future is here

September 30, 2025

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  • Newborn screening is a monumental public health achievement that has saved countless lives by identifying treatable conditions early, exemplified by the personal story of Max, diagnosed with PKU. 
  • The process of deciding which conditions to include in newborn screening panels, like the Recommended Uniform Screening Panel (RUSP), is complex, requiring adherence to criteria (like the Wilson and Younger criteria) that weigh test feasibility, treatment availability, and individual benefit. 
  • The future of newborn screening is rapidly shifting toward whole genome sequencing, which promises to expand the number of screenable conditions exponentially, but this transition raises immediate concerns regarding the dissolution of the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) and the management of vast new datasets. 
  • The shift to genomic sequencing in newborn screening fundamentally changes the process, allowing screening for hundreds of conditions from a single analysis, unlike traditional methods that require developing a new test for each condition. 
  • The GUARDIAN study at NewYork-Presbyterian hospitals is actively screening newborns for over 200 genes using genomic tools, demonstrating the immediate, real-world application of this advanced technology. 
  • Genomic screening introduces complex ethical and logistical questions regarding data ownership, access, and the handling of results for conditions that are not yet treatable, necessitating proactive consideration alongside the potential benefits. 

Segments

Listener Story and Introduction
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(00:00:01)
  • Key Takeaway: Newborn screening provided a life-saving diagnosis for PKU in a baby named Max, highlighting the profound impact of early detection.
  • Summary: Jessica shared her experience receiving a positive newborn screening result for Phenylketonuria (PKU) on day three of her son Max’s life. PKU is a treatable metabolic disorder where the inability to process the amino acid phenylalanine can cause severe brain damage if not managed with a strict diet and medical formula. This early diagnosis, made possible by the screening, ensured Max is now thriving and hitting developmental milestones.
Hosts Welcome and Episode Focus
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(00:07:26)
  • Key Takeaway: The hosts express excitement to explore the process, good, bad, and gray areas of newborn screening, not just individual conditions.
  • Summary: Hosts Erin Welsh and Erin Allman Updike formally welcome listeners to the episode on Newborn Screening for This Podcast Will Kill You. They anticipate discussing the screening process, including its nuances, and introducing an expert guest who is developing the future of newborn screening technology.
Newborn Screening History Overview
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(00:13:13)
  • Key Takeaway: Newborn screening is considered one of the 20th century’s greatest public health achievements, expanding from one or two disorders to dozens via technological advances.
  • Summary: Since its inception 60 years ago, newborn screening has prevented death and disability in countless children globally. The screening panel has grown from just one or two disorders to dozens, with hundreds potentially coming soon via whole genome sequencing. Determining which conditions to include requires careful navigation of treatment options and screening feasibility, often guided by the Recommended Uniform Screening Panel (RUSP) in the U.S.
RUSP and Advisory Committee Dissolution
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(00:16:14)
  • Key Takeaway: The RUSP standardizes screening in the U.S., but its guiding body, the ACHDNC, was recently dissolved, creating uncertainty for adding new conditions like MLD and DMD.
  • Summary: The Recommended Uniform Screening Panel (RUSP) includes 38 core and 26 secondary disorders, managed by the head of HHS and the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). In April 2025, the ACHDNC was dissolved, halting the evaluation of two nominated conditions, Metachromatic Leukodystrophy and Duchenne muscular dystrophy, leaving the future guidance for the RUSP unclear.
NIH Genomic Sequencing Initiative
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(00:20:29)
  • Key Takeaway: The NIH Common Fund launched a $14.4 million collaboratory initiative to determine how to integrate whole genome sequencing into existing state newborn screening programs.
  • Summary: The NIH Newborn Screening by Whole Genome Sequencing Collaboratory Initiative received $14.4 million over three years to figure out how to fold whole genome sequencing into current state public health screening infrastructure. This project focuses on implementation rather than technology development and may eventually supplement or replace the RUSP by establishing a new target gene list.
Origins: Guthrie and PKU Test
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(00:25:31)
  • Key Takeaway: Dr. Robert Guthrie developed the first effective newborn screening test for PKU in 1961, which used a blood spot and could be administered 24 hours after birth, vastly improving upon the previous urine-based test.
  • Summary: The foundation of newborn screening began with Dr. Robert Guthrie’s 1961 letter describing a blood screening technique for PKU, a metabolic disorder causing intellectual disability if untreated. Guthrie’s test was superior because it provided results within 24 hours, unlike the previous urine test that was only accurate six to eight weeks post-birth, potentially allowing irreversible brain damage to occur. Massachusetts mandated this screening in 1963, leading to rapid adoption across 32 U.S. states by 1965.
Ethical Guidelines and Nuance
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(00:30:00)
  • Key Takeaway: The 1968 WHO Wilson and Younger criteria established ethical guidelines for screening, emphasizing the need for a suitable test and existing treatment, though modern genomics introduce significant nuance.
  • Summary: Concerns over the ethical use of knowledge—especially when no treatment exists—led the WHO to publish 10 principles in 1968, known as the Wilson and Younger criteria. Key criteria require a suitable, sensitive test and the existence of a medical intervention, but technological advances have complicated these clear-cut rules, introducing gray areas regarding severity and parental rights to know.
Guthrie’s Motivation and Skepticism
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(00:35:33)
  • Key Takeaway: Robert Guthrie, a microbiologist researching cancer, was motivated by his intellectually disabled son and niece to adapt his bacterial inhibition assay to rapidly screen for PKU, despite initial skepticism from some doctors.
  • Summary: Guthrie, a microbiologist with no background in metabolic disorders, was inspired by his family’s connection to intellectual disability and the limitations of the existing PKU test. He successfully tweaked his bacterial inhibition assay to detect phenylalanine buildup in blood spots, leading to the first rapid screening method. Initial skepticism focused on the diet’s effectiveness and concerns that screening would divert focus from broader social support programs for the disabled.
Screening False Positives and Communication
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(00:44:26)
  • Key Takeaway: High false positive rates are an inherent side effect of maximizing screening sensitivity, causing significant emotional turmoil for parents who often receive little pre-test communication from providers.
  • Summary: Newborn screening is inherently a screening tool, not diagnostic, leading to many false positives necessary to catch all true positives. This process causes financial costs and immense emotional distress for parents during the follow-up period, often compounded by the fact that most doctors do not discuss the screening process with parents before birth.
Defining Screening and System Components
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(00:50:50)
  • Key Takeaway: Screening involves testing asymptomatic populations for diseases before symptoms appear, requiring a complex system encompassing agency decisions, hospital procedures, lab analysis, and follow-up care.
  • Summary: Screening targets asymptomatic individuals, such as testing newborns for disorders they may develop later in life. This process is not a single event but a system dependent on federal/state decisions, hospital exams (like hearing tests), the heel prick blood test, result reporting, diagnostic follow-up, and eventual treatment. The blood test typically occurs around 24 hours of life and utilizes modalities like mass spectrometry.
Screening Criteria and SMA Example
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(00:57:50)
  • Key Takeaway: Adding a condition to a screening list requires meeting strict criteria, including having an appropriate test, existing treatment, and a favorable cost-benefit analysis, as demonstrated by SMA’s addition after its 2016 treatment approval.
  • Summary: The decision to screen for a disorder is rigorous, demanding a test with high sensitivity and a highly specific confirmatory test, alongside an available treatment that can be reasonably accessed. Spinal Muscular Atrophy (SMA) was added to the RUSP in 2018, two years after its treatment became available in 2016, illustrating how treatment availability drives panel expansion.
Genomics vs. Standard Screening
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(01:03:56)
  • Key Takeaway: Genomic sequencing allows screening for numerous disorders simultaneously without incremental test cost.
  • Summary: Switching to genomic sequencing changes the game by allowing screening for many disorders from one analysis, as long as an identifiable gene exists. Unlike traditional screening, adding new conditions to the genomic list does not incur extra testing costs. This contrasts with standard screening, where each new disease requires developing a difficult and costly new test.
Genomic Screening Ethical Hurdles
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(01:04:46)
  • Key Takeaway: Genomic screening raises critical ethical questions about risk data, data ownership, and access.
  • Summary: The same criteria for traditional screening (identifiable gene, asymptomatic stage, treatment) apply to genomic screening, but new questions arise regarding genes linked only to increased risk, not definite disease. Determining who owns and protects the vast amount of data generated by whole-genome sequencing is a major concern. Questions also surround consent regarding access to this information and how long the data should be retained.
GUARDIAN Study Overview
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(01:05:52)
  • Key Takeaway: The GUARDIAN study is screening newborns for over 200 genes using genomic tools in NYC.
  • Summary: The GUARDIAN study is a large, ongoing research project at NewYork-Presbyterian hospitals utilizing genomic sequencing for newborn screening. It screens for over 200 genes associated with conditions affecting young children, significantly expanding beyond the highest state screening panels (like California’s 75 conditions). The study compares genetic findings with existing biochemical screens to ensure accuracy and identify missed conditions.
Parental Experience with Screening
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(01:11:54)
  • Key Takeaway: The follow-up process for parents after a positive genomic screen is similar to standard screening callbacks.
  • Summary: If a potential issue is flagged by genomic screening, parents still undergo a callback process requiring confirmatory testing, which might be genetic or biochemical depending on the suspected condition. This follow-up period, where definitive results are pending, can be trying for parents, though the nature of the follow-up test may differ from traditional methods.
SCID Case Study Success
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(01:13:50)
  • Key Takeaway: Genomic screening identified a severe combined immune deficiency (SCID) missed by the standard chemical screen.
  • Summary: A boy with a genetic mutation for SCID, which was not detected by the existing chemical screen, was diagnosed via the GUARDIAN study. Early detection allowed for a successful bone marrow transplant using a matched sibling donor before life-threatening infections occurred. This case highlights that genomic testing can find actionable conditions missed by current screening panels, leading to cures.
Urgency for Genomic Implementation
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(01:16:27)
  • Key Takeaway: Clinicians feel an urgent need to implement genomic screening widely to capture treatable conditions immediately.
  • Summary: Researchers feel immense urgency to implement genomic screening rapidly because children are currently being born with conditions that could be captured and treated. There is a drive to fill the list of treatable conditions identified by genomics and prepare treatments for them. Simultaneously, ethical questions regarding untreatable syndromes must be confronted in advance to establish future standards of care.
Research Opportunities via Data
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(01:17:45)
  • Key Takeaway: Anonymized genomic databases offer powerful research tools for understanding and curing currently untreatable conditions.
  • Summary: Even for syndromes without current treatments, knowing the genetic basis through screening can motivate research toward finding cures. Anonymizing medical records and sequences allows researchers to query databases to understand the phenotypic results of specific variants. This data access is crucial for understanding disease mechanisms and developing future interventions.