Changing the Time of Newborn Screen Collection A Data-Driven and Safety-Oriented Approach Emeril Santander Michael Kowalski Laure Tessier Jennifer Milburn Pranesh Chakraborty
Objectives Describe current sampling guidelines and the importance of timely screening in the context of Ontario’s universal newborn screening program Describe results of a four-part approach taken to determine safety of earlier screening
Screening for Disease Screening in general: Detects treatable disease Significantly speeding diagnosis & treatment As early as possible Prior to onset of severe or irreversible health outcomes When delivery of treatment is most effective As accurately as feasible Screen Positives likely to be truly affected by disease Screen Negatives likely to be unaffected by disease A cost-effective way to identify elevated risk We screen because we can’t diagnostically test everyone, however everyone is at risk. We accept the tradeoffs of screening to instead extend risk identification to everyone.
Newborn Screening in Ontario Shortly After Birth A small sample of blood is taken
Newborn Screening in Ontario The sample of blood is dropped on to a special type of paper on the newborn screening card These cards are pre-distributed to all neonatal healthcare providers in the province Not just ‘The PKU Test’ Expanded panel in 2006 and 29 genetic diseases now tested based on 100+ biomarkers Central public health laboratory model based in Ottawa Universal population-based screening with >99% of newborns tested .
Newborn Screening in Ontario Health care provider fills out information about the baby on the card, including datetime of birth and collection
Newborn Screening in Ontario The newborn screening sample is sent to Newborn Screening Ontario (NSO) in Ottawa for testing. Overnight courier service is used.
Newborn Screening in Ontario At the lab, several techniques are applied to evaluate for risk of metabolic, immune, endocrine, and other diseases. Up to 1200 samples per day
Newborn Screening in Ontario SCREEN POSITIVE PATIENTS SCREEN NEGATIVE PATIENTS Are referred to specialist care at one of five regional treatment centres Kingston General Hospital Toronto Sick Kids Ottawa Children’s Hospital London Health Sciences Hamilton Health Sciences Diagnostic Testing Healthcare Provider notified Healthcare Provider Receives Negative Report Again, more than 99% of Ontario’s 140,000 yearly births will be negative.
Part II. Sampling and time-sensitive screening
babies are born each year in Ontario Working Against the Clock Aggressive Diseases: Maple Syrup Urine Disease (MSUD) Medium-Chain acyl-CoA dehydrogenase deficiency (MCADD) Propionic Acidemia (PA) Methylmalonic Acidemia (MMA) Galactosemia (GALT) Tyrosinemia (TYR) Citrullinemia (CIT) ASA Lyase Deficiency (ASA) Congenital Adrenal Hyperplasia (CAH) Approximately 140 000 babies are born each year in Ontario ~ 250 babies will have a disease ~1500 babies will screen positive If detected and treated early, affected infants may have health outcomes similar to unaffected infants. If not detected or treated,
The Urgency of Detection Among the 250 infants detected each year truly affected by a screened disorder: 5% – 10% May die in the first week of life 10% – 20% Will be symptomatic in this first week Among the screened disorders, 20 of them have potential to cause irreversible harm in first two weeks of life
The Newborn Screening Sequence
The Newborn Screening Sequence NSO now works 7 days per week New software tracks all packages en-route NSO refers critical patients on weekends BORN-supported electronic referral and diagnostic tracking
24 - 72 h 24 - 48 h Timely Collection Timely Screen after birth Historical Guideline 24 - 72 h after birth New Guideline 24 - 48 h after birth
Part III. Screening earlier, safely New Guideline Systematic Review Longitudinal Analysis Impact Forecasts Review Peer Practices Part III. Screening earlier, safely
A. Reviewing the literature New Guideline Systematic Review Longitudinal Analysis Impact Forecasts Review Peer Practices A. Reviewing the literature
Reviewing the literature – Methods and results 534 records identified in MEDLINE 29 records identified from other sources 5 records after duplicates removed 558 records screened 72 full-texts assessed -Literature search: to determine whether there was any evidence that collecting DBS at 24h of age could increase the risk of false-negative results for disorders on the NSO panel -MEDLINE database search, and identified some articles using other sources -> team’s pre-existing knowledge of existing articles answering our research question, ScienceDirect Cited Srticles and Recommander search tool for those articles, and reference scans of the retained articles -Research question divided into 2 searches: one to find evidence of false-negative results or sensitivity reports with sample collection at 24h of age, one to find evidence of the NSO primary analyte levels in the first 24h of age (to compare them with current NSO cut-offs) -Searches conducted for every disease on the NSO panel except galactosemia and hemoglobinopathies -Records identified with other resources were not identified by our MEDLINE search 12 full-texts included in literature review
Conclusions No evidence that collecting dried bloodspot samples at 24 hours of age would increase NSO’s false-negative rate Some evidence suggests that collecting samples at 24 hours of age would not increase the false-negative rate for PKU and CH (based on analyte values measured at 24 hours of age) Limitations: two reviewers for screening, only one reviewer for full texts (this is a rapid review), search did not seem systematic Next step: turning this into a systematic review
B. newborns with multiple samples New Guideline Systematic Review Longitudinal Analysis Impact Forecasts Review Peer Practices B. newborns with multiple samples
Finding Age Effects on Biomarkers The ideal observational study*: Follow a large sample of newborns With disease and without disease Prick heel of each every hour in the first 72 hours of life Check for differences in biomarker levels by postnatal age Determine if sampling age would change sensitivity or specificity of screening test * We can’t do this.
Finding Age Effects on Biomarkers Instead: Retrospective Cohort 553 newborns between 2010-2015 Sampled more than once in first 72 hours of life ‘by chance’ No obvious reason for multi-sampling Samples linked in system using demographics
Biomarker X Patient 1 Biomarker Value HIGH 24 hours 48 hours 72 hours uL X at T1 X at T2 24 hours 48 hours 72 hours Postnatal Age in Hours
Biomarker X Patient 1 Biomarker Value HIGH 24 hours 48 hours 72 hours uL X at T1 X at T2 24 hours 48 hours 72 hours Postnatal Age in Hours
Biomarker X Patient 1 … Patient 553 Biomarker Value HIGH 24 hours 48 …. HIGH Patient 553 Biomarker Value uL 24 hours 48 hours 72 hours Postnatal Age in Hours
Biomarker X Biomarker X 72h trend Biomarker Value HIGH 24 hours 48 uL 24 hours 48 hours 72 hours Postnatal Age in Hours
No Difference in Screening Performance When Trend is Stable Biomarker X HIGH Screen Positive Cutoff Values above this line are at elevated risk Biomarker Value uL 24 hours 48 hours 72 hours Postnatal Age in Hours
Increased Risk of False Positive Results When Trend is Negative Biomarker X HIGH Screen Positive Cutoff Values above this line are at elevated risk Biomarker Value uL 24 hours 48 hours 72 hours Postnatal Age in Hours
Increased Risk of False Negatives With Upward Trend Biomarker X HIGH Screen Positive Cutoff Values above this line are at elevated risk Biomarker Value uL 24 hours 48 hours 72 hours Postnatal Age in Hours
Thyroid Stimulating Hormone (TSH) Biomarker for Congenital Hypothyroidism(CH) True Negative False Positive True Positive
Thyroid Stimulating Hormone (TSH) Biomarker for Congenital Hypothyroidism(CH) True Negative False Positive True Positive
Postnatal TSH Elevation A well-known endocrine response to birth The postnatal tsh rise begins 30 minutes following birth and is thought to be a response to the cold of the extrauterine environment
Summary Repeating this modelling across all screened biomarkers: Certain endocrine markers will be elevated at an earlier age (false positive risk) Potentially higher referral, recall, & diagnostics Most trends were stable No false negative risks identified
C. Predicting future screening performance New Guideline Systematic Review Longitudinal Analysis Impact Forecasts Review Peer Practices C. Predicting future screening performance
Background & goals Goal: Identify the impacts on screening performance caused by more samples being collected earlier Background: 85% of samples in 2015 were collected 24-48 hours after birth This number has grown by ~ 5%/yr since 2010 (…earlier discharges?) There are no systematic individual differences in infants collected 24-48 hours vs. 48-72 hours.
Background & goals Key points (cont.): Proportional indicators of screening performance in the 24-48h interval have remained stable, even as more samples are collected in this window SPP24-48: 0.01% (screen positive rate) SNR24-48: 99.99% (screen negative rate)
Method & Conclusion To forecast future performance we take the relevant proportions from the 24-48h interval and multiply them by the expected volumes of samples Conclusion: Most referrals will remain at current levels. Certain endocrine referrals may increase, although further optimization may be possible.
D. sampling practices in other screening programs New Guideline Systematic Review Longitudinal Analysis Impact Forecasts Review Peer Practices D. sampling practices in other screening programs
American Sampling Practices Research Question: Is this a common practice in other screening laboratories in North America? Method: Database review (NEWSteps) & survey Results: 93% of US jurisdictions collect newborn screening samples at 24-48 hours.
24 - 48 h Summary & Conclusion after birth Screening is time-sensitive New Guideline 24 - 48 h after birth Screening is time-sensitive Reducing age at sampling is safe, we checked! Certain false positives may occur, but work to mitigate these is ongoing Screening at 24-48 hours is a widely-adopted practice in peer screening programs