Newborn screening as a model for population screening.

1. IntroductionThe incorporation of newborn screening into thestates’ departments of public health represented theformal initiation of population-based predictive medi-cine with the goal of prevention of morbidityandmortalityfrom genetic disease. Starting with a meth-odologybasedonmicrobiology,thebacterialinhibitionassay[1],theﬁeldhasincorporatedfarmoreadvancedtechnologies such as molecular genetic analyses [2–7]and tandem mass spectrometry(MS/MS) [8–12]. Pre-dictionandpreventionarefundamentaltopublichealthandgenomicmedicine.Eﬀectiveintegrationofscreeningacrossthelifespanforgeneticpredispositionanddiseasewill require utilization of advanced technologies andinformation systems, and incorporation of appropriatesafeguardstoprotectautonomy,privacyandconﬁden-tiality.As newborn screening testing menus expand andpopulation-based genetic screening extends throughadulthood, pilot programs must be developed andevaluatedtodeterminetheirabilitytoachievethegoalsand objectives for which theyare designed [13]. Suchpilot programs will require careful design, not onlytoassessthetechnologicalbasesofthesesystems,butalsoto evaluate their impact on the individuals tested. De-terminationofimpactmustincludenotonlytraditionaleﬀectivenessmeasuressuchaschangesinmorbidityandmortalityfrom disease, but also the ethical, legal andsocial implications of testing such as genetic discrimi-nation[14–18].Design and implementation of genetic screeningprogramswillrequirebroad-basedexpertise.Inadditionto the traditional membership on screening programadvisorycommittees, such as medical specialists andsubspecialists, laboratorians, and public health andgovernment oﬃcials, these groups must represent allstakeholders [13]. Aﬀected individuals and their familymembers have the best-informed experience with theprocessandconsequencesofscreening,andtheyshouldbeincorporatedasfullandequalmembers.1.1.RoleofscreeninginpublichealthThe goal of screening has been to identifydiseasebefore irreparable damage is done, to determine indi-viduals whose oﬀspring are at risk for disease, and toevaluate new screening strategies and their potentialimpacts [19–21]. Implementation of these principleswithin a public health paradigm means that theywilltranslate to presymptomatic identiﬁcation of aﬀectedindividuals, recognition of carriers of genetic diseases,andperformanceofresearchtoimprovescreeningpro-grams.Therefore,screeningforgeneticdiseasewillfulﬁllthe public health need of providing an ever-evolving‘‘safety-net’’topredictandpreventdisease.While screening mayinvolve clinical evaluation ofindividuals, here we will be concerned primarilywithlaboratory-based screening programs. By their verynature, such programs will be driven byadvances inlaboratorytechnology. Until veryrecentlypopulation-based screening programs, such as neonatal screening,have relied on biochemical measurements of analytesthathaveincluded:metabolites(e.g.,phenylalanineforphenylketonuria,orgalatoseandgalactose1-phosphatefor galactosemia); hormones (e.g., thyroid stimulatinghormoneand thyroid hormone forhypothyroidism, or17-hydroxyprogesterone for 21-hydroxylase deﬁcientcongenital adrenal hyperplasia); and proteins (e.g.,hemoglobin for hemoglobinopathies, galactose 1-phos-phateuridyltransferaseforgalactosemia,orimmunore-activetrypsinogen(IRT)forcysticﬁbrosis(CF))[21,22].Beginninginthe1980s, thetools ofmolecular genetics