Abstract
For newborn screening (NBS) of lysosomal storage diseases, programs measure enzymatic activities in dried blood spots (DBS) and, in most cases, act on samples where the measurement is below a specific cutoff value. The rate of false positives and negatives in any NBS program is of critical importance. The measured values across a population of newborns are governed by many factors, and in this article we focus on assay imprecision. Assay parameters including the Analytical Range and the Z-Factor have been discussed as a way to compare assay performance for NBS of lysosomal storage diseases. Here we show that these parameters are not rigorously connected to the rate of false positives and negatives. Rather, it is the assay imprecision near the screen cutoff that is the most important parameter that determines the rate of false positives and negatives. We develop the theoretical treatment of assay imprecision and how it is linked to screen performance. What emerges is a useful type of parametric plot that allows for rigorous assessment of the effect of assay imprecision on the rate of false positives and false negatives that is independent of the choice of screen cutoff value. Such plots are useful in choosing cutoff values. They also show that a high assay imprecision cannot be overcome by changing the cutoff value or by use of postanalysis, statistical tools. Given the importance of assay imprecision near the cutoff, we propose that quality control DBS are most useful if they span a range of analyte values near the cutoff. Our treatment is also appropriate for comparing the performance of multiple assay platforms that each measure the same quantity (i.e., the enzymatic activity in DBS). The analysis shows that it is always best to use the assay platform that gives the lowest imprecision near the cutoff.
Highlights
In most newborn screening (NBS) programs, measurement is made on analytes or enzymatic activities present in dried blood spots (DBS) on NBS cards
The problem is confounded by the spectrum of severity of lysosomal storage diseases that present in early infancy and even as toddlers and adults
There are many factors that lead to variation in the enzymatic activity measured in a 3-mm punch of a DBS measured across a population of newborns
Summary
In most newborn screening (NBS) programs, measurement is made on analytes or enzymatic activities present in dried blood spots (DBS) on NBS cards. In cases where a low value of the measurement is characteristic of a disease, for example the activity of an enzyme, the NBS program sets a cutoff value such that newborns displaying an assay value below the cutoff are considered screen-positive in the first-tier analysis. These plots are typically done by binning, whereby one carries out an assay on a large set of newborn DBS (say 100,000), counts the number of newborns who display a certain small span of assay values (say 1.0–1.1 μmol/h/L for an enzymatic assay), and divides this number by the total number of newborns to obtain the fraction of newborns in this assay bin. Neonatal Screen. 2019, 5, x FOR PEER REVIEW have to pass through the origin of Figure 1B, but it will pass close enough to the origin to lead to the skewbinlagn,kancodrrtehceteldo.gT-hnuosr,mthaelPfuDnFcdtiooens nisotsthiallvaeptoprpoapssritahtreo.ugh the origin of Figure 1B, but it will pass Fclaolssee epnoosuitgihvetos athree osorimgienttiomleesadcltaossthifieesdkeawsipnsge, uanddodtheefilcoigen-ncoierms iafltfhuencDtiNonAissestqilul eanpcperoopfrtihatee.relevant gene showFaslsae vpaorsiiatitvioesn atrheatsoims tehtiemleiskecllyasrseifaiesdonasfoprstehuedoddeecfriceiaesnecieins eifntzhyemDaNtiAc ascetqivuietnycethoaft thhaes not reachrheeadlseavnaosnuttfrfigeaeccniehenesdthlyoawlsouswfaficlveiaevrneitalltytioolnocwathulaestveiestlhttheoedclaiiskueesaleystehr.eeDadseoipsneeafnosder.itnDhgeepdoeenncdrtehianesgeaominnoteuhnneztyamomfaortueicnstiadcoutfivariletseyindtzhuyaatlmatic activietnyz(yamnadtipcoascstiivbiltyy o(atnhderpfoascsitbolrys)o,tdheisrefaacsteosrsc)a,ndibseeaeseasrlcyanonbseeetawrlyitohnsseevt ewriethsysemveprteosmyms oprtolmatseorronset with llaetsesrsoenvseertewsiythmlepstsosmevse.rIensythmisptcohmaps.tIenr twhies cdhoapntoetr cwoendsiodneortthcoensseidvearrtihaetisoenvsa;rriaattihoenrs;wraethseprewake only of unsapffeeackteodnlaynodf uanffaefcfetcetdedpaantidenaftfse.cted patients
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