The History of and Advances in Newborn Screening: Where Do We Stand?

P2 L46 on – other issues of primary genomic newborn screening include variable penetrance and timeliness.

Included

P2 Screening Criteria. The work of Wilson and Junger refers to as criteria but in fact they are not; they are considerations to be worked through. So for example ‘as significant health problem’ significance is in the eye of the beholder and does not have a universal reference. ‘Treatment availability’ may mean a treatment exists in another jurisdiction,  exists but very expensive, exists and is universally available to diagnosed infants. This lack of definitions is part of the reason jurisdictions screen for different disorders and claim they meet criteria.

Yes, these are principles, but criteria is often used in the literature. Revised to say principles instead of criteria.

#2.3 Part of the difference between the number of disorders screened by states is different ways of counting. APHL has a workgroup attempting to standardise this, and consider ‘secondary conditions’ chaired by Susan Tanksley Susan.Tanksley@dshs.texas.gov

Incorporated updated from APHL and their task force, examining numbers, counting, and inclusion of secondary conditions.

#2.4A Also genetic inequities in minority populations due to ethnicity limitations of reference databases.

Included. Great suggestion.

#2.4B Might also consider timely provision of information as families move down the screening pathway eg get positive test or diagnosis, and provision of information in an appropriate form.

Incorporated as well as information related to parental stress of false-positive results.

#2.4C ppv varies between disorders and many programmes are working to improve ppv by addition of second-tier tests (analyte ratios eg phe/tyr after raised phe, or MMA, homocysteine etc after raised C3) – is information available about this in USA?

Included secondary/reflex testing concept. Yes, it helps, but there are still quite a few false positives.

#3.4 arguably there is no disorder with variants that show complete penetrance eg there are c.1521_1523delCTT (df508) homozygotes in cftr known to be asymptomatic.

We agree that penetrance is a somewhat subjective term, with differing opinions among authors. We believe that this issue is beyond the topic of this manuscript.

#3.5 this is complicated and a comment about x-ald – widely screened in USA (screen boys or include girls knowing some boys and all girls will be late/no onset of symptoms) might be appropriate here.

There are several that raise concerns, some on the RUSP, some not. We incorporated X-ALD and identification of early and late onset, and variability among males and females.

Line 27: where do I find the reference or the statistic for the 30 to 50 new single-gene disorders added to the list (OMIM)? Update: I found the reference (website?) on line 206, but I still do not find the statistic for 30 to 50 new gene disorders added per month.

Reworded with annual statistics and cited.

Line 41: the statement “… approximately 10% of the conditions with available treatments are currently included”, is that common knowledge or can the authors give a reference?

This is mathematical. If a state screens for 65 disorders and you compare that panel to a WGS that screens for 250 disorders, that’s a 26% difference. If a state screens for 70 disorders and you compare that to a WGS with 700+ disorders, it is about 10%. As such, we presented a range based on that understanding.

Line 45: “Several Pilot Studies using this technology (NGS) are underway in the US and abroad”. Can the authors give some examples on which US states or countries? Do the authors know this first hand, or are they assuming it is happening because of the general interest? Update: Found the same statement and the references are stated in line 224.

Provided a table with some examples of WGS NBS initiatives in the US and abroad.

Line 157: after the word disorders, a period too many (after the reference)

Corrected

Line 158 – 159: consider to revise the parenthesis.

Corrected

Lines 211 – 212: require a reference to back up the statement, or are the authors speaking based on their institutions?

Added citation.

Line 215: typo - genomic sequence (GS) and not as written GC

Corrected

Lines 320 – 323: which groups are the authors referring too? The authors write “above-formulated” but it is not clear for the reader what is in each group (A,B,C)

Clarified by repeating the types.