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What Is “NIPT”? Divergent Characterizations ofNoninvasive Prenatal Testing StrategiesMeredith Vanstonea, Karima Yacoubb, Shawn Winsorc, Mita Giacominia & Jeff Niskerd

a Centre for Health Economics and Policy Analysis and Department of Clinical Epidemiologyand Biostatistics, McMaster Universityb Department of Clinical Epidemiology and Biostatistics, McMaster Universityc Department of Clinical Epidemiology and Biostatistics and Health Policy PhD Program,McMaster University, and Joint Centre for Bioethics, University of Torontod Department of Obstetrics and Gynecology, Schulich School of Medicine and Dentistry,University of Western Ontario, and Children's Health Research InstitutePublished online: 06 Mar 2015.

To cite this article: Meredith Vanstone, Karima Yacoub, Shawn Winsor, Mita Giacomini & Jeff Nisker (2015) What Is“NIPT”? Divergent Characterizations of Noninvasive Prenatal Testing Strategies, AJOB Empirical Bioethics, 6:1, 54-67, DOI:10.1080/23294515.2014.993102

To link to this article: http://dx.doi.org/10.1080/23294515.2014.993102

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Article

What Is “NIPT”? DivergentCharacterizations of Noninvasive

Prenatal Testing StrategiesMeredith Vanstone, Centre for Health Economics and Policy Analysis and Department

of Clinical Epidemiology and Biostatistics, McMaster University

Karima Yacoub, Department of Clinical Epidemiology and Biostatistics,

McMaster University

ShawnWinsor, Department of Clinical Epidemiology and Biostatistics and Health Policy

PhD Program, McMaster University, and Joint Centre for Bioethics, University of Toronto

Mita Giacomini, Centre for Health Economics and Policy Analysis and Department of

Clinical Epidemiology and Biostatistics, McMaster University

Jeff Nisker, Department of Obstetrics and Gynecology, Schulich School of Medicine

and Dentistry, University of Western Ontario, and Children’s Health Research Institute

Background: Noninvasive prenatal testing (NIPT) strategies that analyze cell-free fetal DNA found in maternal blood haveproliferated in the past several years. Many different parties have been involved in the development, evaluation, and diffusionof NIPT, resulting in rhizomatic growth of this technology. Here, we use a technology studies lens to examine the way NIPT hasbeen constructed in informational documents and offer suggestions for ethics analysis. Methods: An inductive qualitativecontent analysis was conducted on 20 documents produced by organizations that claim authority to construct a version of NIPT(13 vendor documents, 7 health professional society documents). Results: Analysis revealed that each document describes adifferent version of the test, offering different claims of purpose, target population, health care professional involvement,relationship to other technologies, fallibility, and risk. Conclusions: The different versions of NIPT technologies entail differentsets of ethical questions and issues. An ethics analysis of NIPT should consider the specific features of the technology underconsideration, which may open the analysis to consider more specific ethical, social, and organizational implications of thattechnology.

Keywords: ethics, noninvasive prenatal testing, prenatal diagnosis, prenatal screening, qualitative content analysis, technology

Noninvasive prenatal testing (NIPT) refers to a strategy ofprenatal testing that analyzes cell-free fetal DNA (hence-forth referred to as cell-free DNA) in maternal blood.While this prenatal testing strategy is becoming increas-ingly available through private and public health careinstitutions, ethical and policy analysis is still developing(Chitty et al. 2012; Schmitz 2013; Vanstone et al. 2014). Inthis article, we use a science and technology studies lens toexamine how NIPT is characterized as a technology byvendors and professional societies, highlighting potentialchallenges for ethical and policy analysis when the

boundaries of NIPT technology are not contextualized in aclear and specific way. We accomplish this by conductinga qualitative content analysis of information documents,using the guiding question: “How is the technology ofNIPT constructed in informational material produced byvendors and professional societies of health careproviders?”

What is NIPT? Most producers, users, and researchersof NIPT would likely agree that it is a way to gain informa-tion about fetal genotype by examining samples of cell-free DNA obtained from the mother’s blood. The same

Address correspondence to Meredith Vanstone, Assistant Professor, Centre for Health Economics and Policy Analysis, McMasterUniversity, CRL 205, 1280 Main St W., Hamilton, ON, L8S 4K1, Canada. E-mail: meredith.vanstone@mcmaster.ca

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Copyright © Taylor & Francis Group, LLC

ISSN: 2329-4515 print / 2329-4523 online

DOI: 10.1080/23294515.2014.993102

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parties may disagree on the required degree of clinicianinvolvement, what type of genetic material could be ana-lyzed (e.g., cell-free DNA, cell-free RNA, placental micro-RNA, genes expressed from extravillous trophoblasts), themethod of analysis (e.g., single-nucleotide polymorphism[SNP]-targeted sequencing, chromosome-selective or shot-gun massively parallel sequencing), reliability of analysis,target population, time of use in the antenatal care path-way, purpose of obtaining this information, and therequirement for other technologies before, during, andafter the use of NIPT.

These diverse characterizations of NIPT may reflect theatypically quick evolution of NIPT (Bianchi et al. 2014) atthe hands of its promoting stakeholders (multiple vendors,business development proposals, certain clinicians, someprofessional organizations). The rapid diffusion of NIPThas been driven by vendors keen to capitalize on parents’desire for a noninvasive test that will help them to avoidhaving a child with certain characteristics such as a partic-ular sex, inherited trait, or trisomy condition (Hill et al.2012; Lewis et al. 2014; Transparency Market Research2014; Yi et al. 2013). As a result of the involvement ofmany different stakeholders, NIPT has grown in manydirections, been proposed for a variety of uses, been linkedto a number of different technologies, and been targeted atmultiple patient populations. In this article, we make theconjecture that the rhizome-like growth of NIPT is notalways explicitly recognized in the scientific and clinicalliterature, where many authors treat their conception ofNIPT as the only way of using this technology, and thatnot examining the specific features of a technology understudy impedes ethical analysis.

Characterizing NIPT as a clearly defined, monolithictechnology not only disguises much of the tension andconfusion about what technology “NIPT” refers to, butalso obfuscates current and potential uses of this technol-ogy from ethical and, ultimately, policy consideration.Understanding the context in which a technology will beused is an important foundation for ethical analysis. Thisfocus on the contextualized use of a technology subscribesto the view that ethical implications are not embeddedwithin the apparatus of the technology, but within the con-text and application of that technology, or the design,meaning, and purpose of that technology (Heitman 1998;Lehoux 2006; Lehoux and Blume 2000; May 2006).

With NIPT, this means that the ethical issues are notrelated to the particular genetic assay techniques used toanalyze the cell-free DNA, but to the construction of aneed for knowledge about the fetal genotype and relatedconstructions of the risks acceptable in gaining that knowl-edge, the claims made about the accuracy of that analysis,the groups who are given (or restricted from) accessingthat analysis, the conditions that are tested for, and theway those conditions are chosen for inclusion in the test,among other considerations. The use of NIPT may be ethi-cally different depending on when it is offered, how thetest fits within the antenatal care pathway, and what

counseling is included with the offer (Deans and Newson2012; Sayres, Allyse, and Cho 2012).

Ethicists are often interested in examining the unin-tended, unexpected, or inevitable “side effects” of a tech-nology, that is, the effects that a technology has outside ofits intended purposes (Giacomini, Winsor, and Abelson2013). Without understanding the particular contextualdetails of how NIPT is used in a particular setting, ethicalconsideration of these types of “side effects” is challeng-ing. This contextual information is needed to understandhow NIPT is changing reproductive care and decisionmaking and the potential impacts for women, clinicians,and people with disabilities. Examining the ways in whichNIPT is implemented may open up new avenues of ethicalinquiry related to its place in the clinical pathway, the roleand actions of health professionals, the impact on patients’lives, the reshaping of antenatal care practices, and thenormative values espoused by the offer of the technologyitself (Giacomini, Winsor, and Abelson 2013; Heath, Luff,and Svensson 2003; Schmitz 2013). This may assist inbroadening ethical consideration of NIPT beyond the com-mon issues of reproductive autonomy, informed choice,and impact on people with disabilities—important consid-erations, but only part of the potential impact of this newtechnology (Schmitz 2013).

METHODS

This study is informed by the theoretical frameworkknown as social shaping of technology (Clausen and Yosh-inaka 2004; Russell and Williams 2002; Wajcman 2010;Williams and Edge 1996). This is a constructivist frame-work that conceptualizes society and technology as mutu-ally constitutive, shaping each other through sociallynegotiated features and meanings (constructs) (Clausenand Yoshinaka 2004; Russell and Williams 2002; Williamsand Edge 1996). We were specifically interested in howvendors and professional societies construct the organiza-tional aspects of NIPT, and how these ascribed structuresaffect what essentially the technology is and what it cando. In turn, the availability or promotion of particular con-figurations of the technology creates new opportunitiesand imperatives for its use, and affects societal views ofnormalcy and health (Parens and Asch 2000; Rapp 1999;Tremain 2005; Vanstone, Kinsella, and Nisker 2014).

To investigate how NIPT is constructed and promoted,we conducted an inductive qualitative content analysis ofprescriptive documents authored by vendors and profes-sional societies. Professional societies and test manufac-turers write and distribute these documents to introduceNIPT’s potential users to what the technology “is” andadvise them on why, when, and how to use it. These care-fully articulated visions provide a unique source forunderstanding key stakeholders’ “organizational versionsof reality” of NIPT (Atkinson and Coffey 2010, 66). Docu-ments both reflect the views of their authors and influencethe views of their audiences (Atkinson and Coffey 2010;

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Miller and Alvarado 2005; Prior 2003), and, in doing so,participate actively in shaping NIPT practices and the tech-nology’s role in health and health care.

The guiding question of this study is, “How is NIPTconstructed in informational material produced by manu-facturers and professional societies of health careproviders?” We qualitatively analyzed the content of thesedocuments for how NIPT is described to its users, andwhat claims are made about the purpose, capabilities, andaudience of this technology. We also analyzed argumentssupporting key claims.

Data Collection1

Following constructivist interpretive methodology, weapproached NIPT informational materials as social interac-tions between key authors (professional societies, manu-facturers) and audiences (providers, patients). Weanalyzed the various ways each interaction constructsNIPT, with particular attention to the role of authors’assumptions about target audiences and their interests(Garfinkel 1967; Hodder 2003). These two primary sourcesof education about NIPT—professional statements andeducation materials—often serve as authoritative bases forfurther constructs to be found in, for example, media cov-erage, individuals’ opinions, and so on. In this study, wefocus on the primary “authoritative” materials.

Professional societies typically publish their statementsin peer-reviewed journals or other peer venues, and expectreaders to be providers or other health-system professio-nals. Health care professionals have reported nearly unani-mous reliance on these guidelines when offering NIPT(Sayres et al. 2011). Manufacturers publish their educa-tional materials publicly, but tailor them and direct pro-viders and lay readers to different versions. Thesedifferentially crafted documents reflect important assump-tions about who the different readers are and the distinc-tive knowledge, experience, and values they bring tointerpreting the content (Atkinson and Coffey 2010).

We systematically collected all current (as of January31, 2014) versions of English-language documents in eachcategory: professional statements, manufacturer informa-tion for providers, and manufacturer information for lay-people. Manufacturers’ materials were downloaded fromtheir websites. NIPT is marketed globally by seven compa-nies: Sequenom (MaterniT21 test), Ariosa (Harmony test),Illumina (Verifi test), BGI (Nifty test), Lifecodexx (Praenat-est/Prenatest test), Berry Genomics (BambniTest) andNatera (Panorama test). If a company offered an informa-tion brochure or pamphlet on its website, we used thatsource; if not, we used the relevant webpages. The sectionson webpages that were selected directed information

about the test at pregnant women and/or health careproviders.

We successfully collected educational materials forboth audiences from six companies. Berry Genomics onlyprovides one source of information, which we categorizedas aimed at providers, given the level of scientific detailprovided. We analyzed six documents for laypeople andseven for providers (Table 1).

We collected professional society statements fromEurope, Australia, New Zealand, Canada, and the UnitedStates through searches of guideline databases (NationalGuideline Clearinghouse, Canadian Medical AssociationInfobase, Guideline International Network) and by search-ing the websites of the relevant member organizations ofthe Federation of International Gynecology and Obstetrics(FIGO). We used search terms including “non-invasiveprenatal diagnosis,” “non-invasive prenatal test,” “non-invasive prenatal screening,” and “cell-free DNA.” State-ments were included if they were publicly available, themost current versions, addressed noninvasive prenataltesting, were written in English, included recommenda-tions for clinical practice, and were produced by an associ-ation of health care providers.

We retrieved seven eligible professional statements,although one mentions NIPT only very briefly (RoyalAustralian and New Zealand College of Obstetricians andGynecologists 2010). Professional society statements areshown in Table 1 (American College of Obstetricians andGynecologists 2012; Benn et al. 2013; Chitty and Crolla2009; Devers et al. 2013; Gregg et al. 2013; Langlois andBrock 2013; Royal Australian and New Zealand Collegeof Obstetricians and Gynecologists 2010). Our search wascompleted January 31, 2014. The British Royal College ofObstetrics and Gynecology published an updated state-ment in March 2014; this was not included in our analy-sis, but it may be of interest to readers (Soothill and Lo2014).

Analysis

Qualitative content analysis requires that analysis followsthree typical phases: immersion, reduction, and interpreta-tion (Atkinson and Coffey 2010; Forman and Damschroder2008; Miles, Huberman, and Salda~na 2013). We accom-plished reduction and interpretation by borrowing codingtechniques from constructivist grounded theory (Charmaz2006).

Analysis began with an open-coding stage involvingclose reading and line-by-line coding followed by increas-ingly focused coding and recoding stages; two researchersconducted the coding. Each coding stage iterated with fullteam review and discussion of coding reports, emergingcategories, and findings. Coding was guided in part bysensitizing concepts intended to capture key organiza-tional features of diagnostic technologies, including envi-sioned users, purposes of testing, and NIPT’s relationshipto other technologies (e.g., other diagnostics, or therapeutic

1. Editor’s note: Some of the materials are no longer available onthe websites and/or these websites have become inactive. Thoseinterested in reading the original materials should contact the cor-responding author.

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interventions). Constant comparative analysis was used toanalyze similarities and differences between authors,intended audiences, categories of information, and sup-port for claims, and also to identify potential contentabsent from some documents.

The key features (envisioned users, purposes of test-ing, relationship to other technologies) were expandedinto subcodes by document type. These codes capturedmore specific information and allowed for interpretiveanalysis and the comparison of documents on very

Table 1. Data sources by type

Category OrganizationTest name/

title of guidelines Citation

Vendor documents Ariosa Diagnostics Harmony Ariosa Diagnostics 2013bfor providers BGI Health Nifty BGI Health 2014b

Berry Genomics BambniTest Berry Genomics 2013Illumina Verifi Illumina 2014bLifecodexx PraenaTest/Prenatest Lifecodexx 2013bNatera Panorama Natera, Inc. 2014Sequenom MaterniT21 Sequenom 2013

Vendor documents for Ariosa Diagnostics Harmony Ariosa Diagnostics 2013apatients BGI Health Nifty BGI Health 2014a

Illumina Verifi Illumina 2014aLifecodexx PraenaTest/Prenatest Lifecodexx 2013aNatera Panorama Natera, Inc. 2013Sequenom MaterniT21 Sequenom 2013

Professional SocietyStatements

American College of MedicalGenetics

ACMG statement onnoninvasive prenatalscreening for fetalaneuploidy

Gregg et al. 2013

American College ofObstetrics and Gynecology

Noninvasive prenatal testingfor fetal aneuploidy:Committee Opinion 545

American College ofObstetricians andGynecologists 2012

International Society forPrenatal Diagnosis

Position statement from theaneuploidy screeningcommittee on behalf of theboard of ISPD

Benn et al. 2013

National Society of GeneticCounselors

Noninvasive prenataltesting/noninvasiveprenatal diagnosis: theposition of NSGC

Devers et al. 2013

Royal Australian and NewZealand College ofObstetricians andGynecologists

Prenatal screening for fetalabnormalities

Royal Australian and NewZealand College ofObstetricians andGynecologists 2010

Society of Obstetricians andGynecologists of Canada

Current status in noninvasiveprenatal detection of Downsyndrome, trisomy 18 andtrisomy 13 using cell freeDNA in maternal plasma

Langlois and Brock 2013

Royal College of Obstetriciansand Gynecologists (Britain)

Noninvasive prenataldiagnosis using cell-freeDNA in maternal blood

Chitty and Crolla 2009

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Table 2. Examples of how documents portray wider and narrower uses of NIPT

Wide use Examples of wide use Narrow use Examples of narrow use

Target population � Any/all pregnanciesor criteriaunspecified

“Women withpregnancies of atleast 10 weeksgestational age”(Ariosa Diagnostics2013)

�High-risk pregnancies� Singleton pregnancies

only

“Should not be offeredto low-risk women orwomen withmultiple gestationsbecause it has notbeen sufficientlyevaluated in thesegroups” (AmericanCollege ofObstetricians andGynecologists 2012)

Conditions �Numerous anomalies�None specified� Fetal sex

“Certain conditions thatcould affect thebaby’s health”(Natera, Inc. 2013)

� Trisomy 13, 18, 21� Particular sex

chromosomeconditions

“Risk assessment islimited to specificfetal aneuploidies(trisomy 13, 18, 21) atthis time. Someplatforms also screenfor sex chromosomeabnormalities”(Gregg et al. 2013)

Risk � Eliminates risks ofconventional tests

�None discussed

“There is NO RISK tothe fetus undergoingthe test” (BGI Health2014b)

�Many specific risksrelated to inaccuracy

� Lack of evidence forparticular uses

� Issues with qualitycontrol andstandards

� Chance of test failure,need for redraw

“cffDNA testing fails toprovide a result in asmall percentage ofwomen” (Langloisand Brock 2013)

Outcomes � Reassurance� “Undisturbed. . .

pregnancy”� Information for

unspecified“decisions,”“options”

“Knowledge isempowering”(Sequenom 2013a)

� Personalizedinformation aboutrisk

� Information fordeciding aboutfurther (diagnostic)testing

“Panorama gives you apersonalized riskscore” (Natera, Inc.2013)

Interventions inevent of a positiveresult

�None mentioned, orunspecified“decisions”

“An inconspicuousresult broughtimmense relief aboutthe health of theirunborn child to themajority of thesewomen (98%)” [2%receiving positiveresult not mentioned](Lifecodexx 2013a)

� Further testing “No irrevocableobstetrical decisionshould be made inpregnancies with apositive non-invasiveprenatal testingresult withoutconfirmatoryinvasive diagnostictesting” (Langloisand Brock 2013)

Providers � Physicians� Unspecified health

care providers

“Talk to yourhealthcare providerbefore you decide if

� Specialist physicians� Genetic counselors

“PrenaTest cangenerally only beoffered by doctors

(Continued on next page)

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specific features. As an example of the codes that weredeveloped, the “purpose” category was expanded inpatient pamphlets to include codes about what the testcan detect, what it cannot do, the timeliness of informa-tion, the potential for reassurance, the assumption thatinformation is always desired, the undesirable consequen-ces of other tests that may be avoided through NIPT, andthe questions that couples have that may be answered bythe test.

From this wide array of descriptive codes, we devel-oped an interpretive schema that described the range ofways that NIPT was constructed. We then recoded eachinstance as belonging to a “wide” or “narrow” use of the

technology to create the theory presented in the results.Table 2 provides an illustration of how different types ofdata from each category subscribed to a wide or narrowuse of this technology. N-Vivo 10 (QSR International) soft-ware was used to manage the data.

As all of our data were publicly available, researchethics approval for this study was not necessary.

RESULTS

Each document we reviewed described a particular ver-sion of NIPT. There are significant discrepancies and somedirect contradictions across the different documents’

Table 2. Examples of how documents portray wider and narrower uses of NIPT (Continued)

Wide use Examples of wide use Narrow use Examples of narrow use

the HarmonyPrenatal Test isappropriate for you”(Ariosa Diagnostics2013)

who fulfill therequirements listedunder s.7,paragraphs 1 and 3,in other words,human geneticsspecialists, or otherdoctors who (havingacquired specialistqualification oradditional licensing)are qualified toperform genetictesting in theirspecialty areas.”(Lifecodexx 2013b)

Fallibility � Implied certainty� General disclaimer� Lack of statistics or

use of non-probabilistic statistics

� Accuracy informationpooled across allconditions

“No test is perfect butNIFTY has anaccuracy rate ofgreater than 99.9%for all three Trisomyconditions” (BGIHealth 2014a)

� Explicit uncertainty� False positive rates� False negative rates� Condition-specific

statistics� Inability to detect

mosaicism,translocations, etc.

“Sensitivity andspecificity is notuniform across allchromosomes”(Gregg et al. 2013)“cffDNA testing hasa higher rate of falsepositive result thancurrent diagnostictests” (Langlois andBrock 2013)

Clinical purpose � Vague “testing” terms� Diagnosis

“MaterniT21 PLUS testis a noninvasiveprenatal test thatdetects fetalchromosomalabnormalities”(Sequenom 2013b)

�High-risk screening “NIPT should be anoption as a second-level contingentscreening test (after apositive result fromcurrently used serumand ultrasoundscreeningtechniques)”(Langlois and Brock2013)

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descriptions of NIPT, as well as several similarities. NIPTis described with many types of information, such as thepurpose, relationship to other technologies, target popula-tion, recommendations for counseling, accuracy, and falli-bility. Each document source portrays NIPT along theseand other categories, constructing a distinct version of thetechnology.

Looking at the different versions of NIPT across sour-ces, various related but different technologies are identi-fied. These related descriptions of the technology fall alonga spectrum, with different documents calling upon a vari-ety of wider and narrower range of uses depending on thecategory of information being used. On one end of thespectrum, “narrow” descriptions of NIPT prescribe a veryconstrained way of using this technology, with clearlydefined target population, purpose, and relationship toexisting prenatal testing technologies. On the other end ofthe spectrum, “wide” uses of NIPT are more vague abouthow the technology might be used and encompass agreater number or variety of potential uses. The versionsof NIPT identified in each particular source document donot fall squarely into either end of the spectrum, but existsomewhere along the continuum. Table 2 summarizes thedifferent ways in which wide and narrow uses of NIPT areconstructed.

Characterizations of “Narrow” Uses of NIPT

Narrow uses for NIPT were most commonly found indocuments produced by professional societies and in thesmall number of vendor pamphlets that made explicit ref-erence to professional society documents (e.g., Praenatest).Many statements encouraging a narrow use of NIPT werejustified by reference to the evidence available for that use.In some instances, a wider use of the technology was dis-couraged by these professional society documents becauseof a lack of evidence.

Narrow Use Stereotype

Here, NIPT is considered a screening test of uncertainaccuracy. It should only be used by women with single-ton pregnancies who are at increased risk for a limitednumber of conditions. “Increased risk” is determined bythe physician or a genetic counselor and may take intoconsideration factors such as test results from earlierscreening tests, maternal age, or previous trisomy preg-nancies. The main purpose of using NIPT is to decidewhether or not to proceed with invasive diagnostic test-ing. A negative result after NIPT may make a woman feelmore comfortable choosing not to engage in invasivediagnostic testing. A positive result from NIPT should beconfirmed with invasive testing. The narrow use docu-ments describe the need for clinician involvement incounseling before and after NIPT and specify that agenetic counselor should be involved if a positive resultis received.

Purpose

Documents espousing a narrow use of NIPT are clear thatthe purpose of the test is to screen for various conditions toprovide information to assist in the decision of whether ornot to pursue invasive diagnostic testing. This stance istypical in professional society documents:

Maternal cffDNA screening is an emerging technology thatcan provide highly effective prenatal screening for Down syn-drome, trisomy 18 and possibly trisomy 13 in high riskwomen. It is not a replacement for the analysis of amnioticfluid cells or CVS. (Benn et al. 2013, 10)

This stance is uncommon among patient brochures,with one exception: The patient brochure for the Verifi teststates that the purpose is to “help women and their pro-viders decide whether to have an invasive diagnosticprocedure” (Illumina 2014a).

Relationship to Other Technologies

In the “narrow” characterization of NIPT, there is a clearrelationship between NIPT and other prenatal screeningand diagnostic tests. Many documents describe a positiveresult from initial prenatal screening tests as one possibleimpetus for NIPT testing (BGI Health 2014a; Illumina2014b; Lifecodexx 2013a; 2013b; Natera, Inc. 2014). Somedocuments are explicit that positive results from NIPTshould be confirmed with further invasive testing (Illu-mina 2014b; Lifecodexx 2013a; 2013b), especially the pro-fessional society statements, most of which emphaticallystate that confirmatory invasive testing is required(American College of Obstetricians and Gynecologists2012; Benn et al. 2013; Devers et al. 2013; Gregg et al. 2013;Langlois and Brock 2013). For example:

NIPT results should not be considered diagnostic, and anyabnormal results should be confirmed through a conventionalprenatal diagnostic procedure, such as chorionic villus sam-pling or amniocentesis. (Devers et al. 2013, 294)

Screening or Diagnosis

Professional society documents are explicit that there is notsufficient evidence to support the use of NIPT as a diag-nostic test, so it should be considered a screening test only(American College of Obstetricians and Gynecologists2012; Benn et al. 2013; Devers et al. 2013; Gregg et al. 2013;Langlois and Brock 2013), and patients “should be offeredinvasive prenatal diagnosis for confirmation of results”(American College of Obstetricians and Gynecologists2012, 1).

The American College of Medical Geneticists even rec-ommends using the acronym “NIPS” to emphasize that itis “a screening test . . . For women seeking a definitivediagnosis, invasive procedures for diagnostic testing, suchas amniocentesis or chorionic villus sampling, should beoffered” (Gregg et al. 2013, 396). This is not echoed by

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most vendor documents, with only a few explicitly statingthat NIPT is a screening test (Illumina 2014b)—for exam-ple, “The results of the MaterniT21 PLUS test, althoughhighly accurate, are not considered diagnostic” (Sequenom2013b). Others imply it by stating that their test “assessesthe risks” of trisomy (Ariosa Diagnostics 2013a; 2013b) orby comparing their test to other screening tests instead ofdiagnostic tests (Natera, Inc. 2014).

Target Population

A narrower use of NIPT states that it is only recommendedfor women who are known to have increased risk for fetalaneuploidy, potentially by reason of advanced maternalage, prior positive screening results, or previous aneuploidpregnancies (American College of Obstetricians and Gyne-cologists 2012; Benn et al. 2013; BGI Health 2014a; 2014b;Devers et al. 2013; Langlois and Brock 2013; Illumina2014a; Lifecodexx 2013a; Natera, Inc. 2013; Sequenom2013b). Several professional society documents are clearthat this test “should not be offered to low-risk women orwomen with multiple gestations because it has not beensufficiently evaluated in these groups” (American Collegeof Obstetricians and Gynecologists 2012, 2). A narrow useof NIPT limits it to singleton pregnancies (American Col-lege of Obstetricians and Gynecologists 2012; Benn et al.2013; Lifecodexx 2013b). This is also attributed to“insufficient information to know how well the test willperform in multiple gestation pregnancies that are discor-dant for trisomy” (Benn et al. 2013, 7).

Fallibility

There were many limitations of the test mentioned by pro-fessional society documents, including:

� Lists of conditions NIPT does not detect (American Col-lege of Obstetricians and Gynecologists 2012; Deverset al. 2013; Gregg et al. 2013), some of which are detectedby traditional screening or invasive testing (Gregg et al.2013; Langlois and Brock 2013).

� Lack of evidence of efficacy in particular populations(American College of Obstetricians and Gynecologists2012; Benn et al. 2013; Chitty and Crolla 2009; Deverset al. 2013; Langlois and Brock 2013).

� Fallibility of existing validation studies (Benn et al. 2013;Chitty and Crolla 2009); sensitivity and specificity ratesare not equal across all trisomy conditions (Gregg et al.2013).

� Issues with independent laboratory standards and qual-ity control (Benn et al. 2013; Langlois and Brock 2013).

� Longer time to receive results from NIPT than invasivediagnostic testing (Gregg et al. 2013).

� False negative and positive rates (American College ofObstetricians and Gynecologists 2012; Benn et al. 2013;Devers et al. 2013; Gregg et al. 2013; Langlois and Brock2013).

� The possibility of the need to redraw blood and retest ifthe percentage of cell-free DNA retrieved is low, morelikely in women of higher BMI and in those in earlierstages of pregnancy (American College of Obstetriciansand Gynecologists 2012; Benn et al. 2013; Gregg et al.2013; Langlois and Brock 2013).

� Variability in accuracy between brands of NIPT due tothe use of proprietary bioinformatics, the performance ofwhich requires more evaluation to determine which ismost effective (Benn et al. 2013; Gregg et al. 2013).

Some of these limitations are mentioned in the vendordocuments for providers, especially false negative andfalse positive rates (BGI Health 2014b; Illumina 2014b, Life-codexx 2013b; Natera, Inc. 2014; Sequenom 2013b) and theconditions not tested for (Illumina 2014b; Lifecodexx2013b; Natera, Inc. 2014; Sequenom 2013b). Interestingly,both professional guidelines and vendor documents paymore attention to the possibility of false positive resultsthan false negative results, even though both are a possibil-ity. For example, both Harmony and MaterniT21 give falsepositive statistics in their provider brochures, but do notmention the possibility or probability of false negativeresults (Ariosa 2013b) or only make reference to the ideathat “a negative test does not ensure an unaffected preg-nancy” (Sequenom 2013b), which some may understand tomean that NIPT detects only a limited number ofconditions.

Few vendor documents mention potential for retest, asPanorama does: “In our blinded international validationtrial, lead investigator Kypros Nicolaides, MD, determineda 5.4% no call rate. In internal studies, Panorama redrawrates have been between 5–6%” (Natera, Inc. 2014). Prae-natest also mentions the possibility of retest (Lifecodexx2013a).

Characterizations of “Wide” Uses of NIPT

Wider uses are characterized in two ways: through explicitstatements about wide use and through ambiguous orvague statements that allude to wider potential usages.For instance, if the target population is not discussed in avendor pamphlet, some readers may understand the targetpopulation to be all pregnant women. Wider uses for NIPTwere most commonly found in vendor pamphlets.

Wide Use Stereotype

On this reading, NIPT is a simple and very accurate testthat can be used early in pregnancy by any pregnantwoman to reliably identify the presence or absence of alarge number of trisomy and sex chromosome conditions.This test overcomes the weaknesses of existing prenataltests by offering very accurate information with no physi-cal risk to the fetus. The purpose of this test is to makeavailable information that will provide reassurance, relief,and additional “options” to women. This test will alsoallow women to avoid the physical risk of miscarriage or

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infection associated with invasive testing such as amnio-centesis. This test is facilitated by physicians, who, thedocuments imply, should provide information on the ben-efits and limitations of this test to help a woman identifywhether or not she wishes to take this test.

Purpose

A wide use for NIPT is characterized by very vague state-ments about the purpose of NIPT with positive phrasessuch as “peace of mind” (Natera, Inc. 2013), “reduce fear”(Lifecodexx 2013a), or “knowledge is empowering”(Sequenom 2013a). These platitudes were also present insome vendor documents for providers. For example,MaterniT21 tells providers that “Expectant couples areoften overwhelmed with information. They’re anxious.They’re worried. And they’re looking to you for answers”(Sequenom 2013b). Professional society documents werenot as likely to address the issue of worry or anxiety,although the International Society for Prenatal Diagnosis(ISPD) position statement did state that “all approaches torisk assessment appear to provide an opportunity to re-assure most women that their fetus is unlikely to beaffected by a chromosomal disorder” (Benn et al. 2013, 2).

All documents mention that the purpose of NIPT is toprovide information about the presence of particular con-ditions, giving at least some information about the condi-tions included in the test. However, the amount and detailof the information about conditions vary significantly,from brief mentions that NIPT tests for “certain geneticconditions such as Down syndrome, Edwards syndromeand Patau syndrome” (Natera, Inc. 2013) to more detaileddescriptions of what a chromosome is and what trisomy21, 18, and 13 are like: “Children with Down syndromehave delays in both intelligence and development. Babieswith Down syndrome also have higher chances for healthproblems” (Sequenom 2013a).

The documents rarely address the issue of why awoman might want information about the likelihood of atrisomy condition or sex chromosome abnormality or whatoptions are available in the event of a positive result. Inpatient brochures, this information is conspicuouslyabsent, sometimes obviated by comments addressing whatmight happen in the event of a negative finding. For exam-ple, the PraenaTest patient brochure says that a negativeNIPT test will “help reduce fears and ensure an undis-turbed course of pregnancy” (Lifecodexx 2013a). In pro-vider brochures, we see language such as “giving thepatient and physician ample time to make a fully educatedposition on how to proceed” (BGI Health 2014b) or “makewell informed decisions” (Sequenom 2013b), rather thandetails about what options are available.

Relationship to Other Technologies

NIPT is most frequently compared to prenatal screeningtests (e.g., integrated prenatal screening, maternal serumscreening) and invasive diagnostic tests (e.g.,

amniocentesis, chorionic villus sampling). Documentsespousing a “wide” use of NIPT tend to emphasize it as asubstitute for other prenatal tests, either explicitly, by stat-ing that NIPT can help avoid invasive testing (BGI Health2014a) or implicitly, by favoring NIPT in a direct compari-son. For example, the Harmony patient document states:

other screening tests such as serum blood tests and ultra-sound are also non-invasive, but have false positive rates ofup to 5% and miss detection of up to 30% of fetal trisomy 21cases. . . . Diagnostic tests such as amniocentesis or chorionicvillus sampling (CVS) are accurate for detecting fetal triso-mies, but they are invasive and pose a risk for fetal loss.(Ariosa Diagnostics 2013a)

This brochure does not explicitly state that Harmony isa replacement for these tests, and it uses language (“assessthe risk”) that some readers may understand to implyscreening, but it does not state that Harmony should beused in conjunction with any other test. While readerswith a comprehensive knowledge of prenatal testing mayunderstand this, some readers may perceive that Harmonyis a substitute for both screening and diagnostic tests.

Screening or Diagnosis

There is significant tension around the issue of whetherNIPT results are accurate enough to be diagnostic orwhether NIPT should be considered a screening test.Many vendor documents (for both patients and providers)skirt the screening/diagnosis issue by using words such as“detect,” “test,” “evaluate,” or “assess,” thereby avoidinghaving to declare whether their test is for screening ordiagnosis (Ariosa Diagnostics 2013a; 2013b; BGI Health2014a; 2014b). These vendor pamphlets sometimesdescribe the role of further invasive testing as “for elabo-ration” rather than confirmation of NIPT results.

For example, the Praenatest patient brochure statesthat “further examination is necessary to diagnose agenetic reason for the trisomy”(Lifecodexx 2013a). Mater-niT21 and Panorama sidestep the issue of whether theirtest is intended for screening or diagnosis, avoiding lan-guage that implies either purpose and not mentioning theneed for additional testing to confirm diagnosis (Seque-nom 2013a; 2013b; Natera, Inc. 2013). Berry Genomicsstates that their test is “being increasingly requested as theprimary prenatal diagnostic test” (Berry Genomics 2013).The Royal Australian and New Zealand College of Obste-tricians and Gynecologists lists NIPT under the heading of“Diagnostic Testing,” although notes that its role “remainsundefined” (Royal Australian and New Zealand Collegeof Obstetricians and Gynecologists 2013).

Target Population

The documents communicate different target populationsfor NIPT. The widest use of NIPT describes the target pop-ulation as any pregnant woman (Ariosa Diagnostics 2013a;

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2013b), including those with twin or multiple gestations(Ariosa Diagnostics 2013a; Illumina 2014a; Sequenom2013b). Some documents specify other populations whomay be interested in NIPT, including women who con-ceived via in vitro fertilization (IVF) or who have used eggdonors (Ariosa Diagnostics 2013b; BGI Health 2014b; Illu-mina 2014b; Sequenom 2013b). Unlike other professionalstatements, the American College of Medical Geneticistsdoes not limit its discussion of NIPT to women atincreased risk for aneuploidy (Gregg et al. 2013).

Fallibility

In comparison to documents from professional societies,those from vendors targeting patients identified the fewestnumber of limitations or ways that NIPT is fallible, oftenmentioning only that “no test is perfect” (BGI Health 2014a)and suggesting that women ask their doctor about its limita-tions (Sequenom 2013a). When such language is surroundedwith statements about “clear, powerful results” (Sequenom2013a), this deemphasizes the limitations of the test.

Other common statements about fallibility includemention of what is not tested for (e.g., mosaicism, partialtrisomies, translocations) (Ariosa Diagnostics 2013a) or astatement about negative results not ensuring an unaf-fected pregnancy (Illumina 2014a; Sequenom 2013a). Men-tions of false positive rates and false negative rates wereoften minimized with language such as “false positive andfalse negative results may occur in rare cases” (Sequenom2013a) or “of the 95,000 NIFTY tests performed so far, therehave been zero cases of false-negative results and a false-positive rate of five one-thousandths of one percent(0.005%)” (BGI Health 2014a).

DISCUSSION

In our analysis of vendor and professional society docu-ments, we identified a disjuncture between vendor andprofessional society claims about NIPT. Each documentdescribed NIPT in a slightly different way, constructing itsown version of the technology that varied according topurpose, target population, fallibility, and relationship toother technologies, among other considerations. The mostcommon area of disagreement between the two groups iswhen and how NIPT should be used, with potential usesvarying widely from first-tier screening for all pregnantwomen to second-tier screening for only women known tobe at high risk of particular trisomy conditions.

Given the variety of ways NIPT is characterized in thedocuments we reviewed, we suggest that it can be consid-ered to be multiple technologies employing various strate-gies of analyzing cell-free DNA via maternal blood. Weconsider “technology” in the vein of social shaping of tech-nology (SST) to be not just an object or technique, but anintervention with inherent social, economic, organiza-tional, and political implications (Lehoux 2006; Williamsand Edge 1996). This definition moves beyond an

understanding of what an object is to look at how thatobject is employed, including the way it is organizationallyconstructed with a particular purpose, target population,and resulting effects on users (Bijker et al. 2012; Oud-shoorn and Pinch 2005).

In the case of NIPT, the techniques are different, andthis is acknowledged by several of our documents, typi-cally when discussing the evidentiary base, noting, forinstance, that comparative effectiveness studies of the pro-prietary bioinformatics should be completed (Gregg et al.2013), or that differences in methodology and sequencingdata analysis prevent summing of results from multiplestudies (Langlois and Brock 2013). The question becomeswhether, and to what extent, the different genetic analysistechniques create different technologies.

Currently, the documents treat NIPT as a single tech-nology, even when acknowledging that different analyticaltechniques are used. They construct different versions ofhow this “NIPT” should be employed, without differenti-ating the relationship between analytical technique andproposed use. None of the documents suggest that SNP-targeted sequencing technologies (e.g., Panorama) shouldbe used differently from chromosome selective array tech-nologies (e.g., Harmony) or shotgun massively parallelsequencing technologies (e.g., MaterniT21, Verifi). Instead,they describe a single version of an “NIPT” technology,with its own implications for purpose, relationship to othertechnologies, risk, and outcomes.

Themain result of our analysis is that the way these sin-gle “NIPT” technologies are constructed is different acrossthe documents, revealing that “NIPT” may be most accu-rately considered an umbrella term for multiple relatedtechnologies. The ambiguity aroundwhat NIPT technologyis, how it is used, and what effects it may have may be trou-blesome for ethics analysis of these technologies.

Published ethical analyses so far reflect this dissonancein the definition and use of NIPT and handle this issue indifferent ways: considering potential uses of NIPT not yetclinically available (de Jong et al. 2009); acknowledgingthe uncertainty of the technology and relying on assump-tions (e.g., of accuracy) to characterize NIPT for the pur-pose of ethical analysis (Benn and Chapman 2009);choosing a particular vendor’s version of NIPT to critique(Kaposy 2013); identifying the relationship between ethicalconsequences and the point in the antenatal pathway atwhich NIPT is used (Deans and Newson 2012; Schmitz2013; Schmitz, Netzer, and Henn 2009); and acknowledg-ing the likelihood of technology expansion whilehighlighting potential issues of many different types of usewithout defining a particular use (Allyse et al. 2013).

As a result of the variety of ways NIPT is described, itis difficult to contextualize this technology for ethical anal-ysis. Contextualization of a technology is a constructiveactivity, with the analyst constructing and negotiating theboundaries, divisions, and trade-offs between technologies(Giacomini 1999). Whether or not the act of contextualizinga technology is acknowledged, it takes place through

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activities such as delineating the scope of the disease orproblem the technology aims to address; defining relevantmanagement, economic, and implementation issues; defin-ing relevant patient populations; and so on (Giacomini1999; Lehoux and Blume 2000; Levin et al. 2007).

The vendor and professional society documents weexamined participate in this work of contextualizing thetechnology. The contextualization work done by thesedocuments provides the foundation for future assessmentor evaluation of the technology, and therefore shapes theoutcomes of that endeavor (Giacomini 1999).

Contextualizing a technology before evaluating or ana-lyzing it is important because it enables the analyst toexamine how that technology will operate as part of alarger technological system, thus opening the possibility ofconsidering the impact that technology may have on allthe other elements in that system as it interacts, substitutes,complements, or conflicts with other components of thesystem (Hughes 2012). The effect NIPT will have on theprenatal care system will depend on when, how, and withwhat supports it is introduced. Analyzing the ethicalimplications of NIPT without considering these specificcontextual issues tends to result in the ethical analysis ofabstract concepts (e.g., reproductive autonomy, informedchoice) to the exclusion of specific issues (e.g., availabilityof care for people in rural and remote locations) (Sayres,Allyse, and Cho 2012; Schmitz 2013; Silcock et al. 2014).

Both abstract and specific issues are important toinclude in an ethical analysis of a health technology. Futureethical analysis of NIPT may wish to examine the impactsof specific versions of this technology, such as the involve-ment of industry and activist stakeholders, implications ofan expanded range of conditions, availability of care forpeople in rural and remote areas, and change in patient–provider and generalist–specialist interactions (Sayres,Allyse, and Cho 2012; Schmitz 2013; Silcock et al. 2014).

The pace of change witnessed so far in the develop-ment of NIPT (Bianchi et al. 2014) and the lack of regula-tion and consensus standards mean that a singleauthoritative definition of NIPT is not currently available,requiring those who wish to study the technology (e.g., forethical analysis or health technology assessment) to articu-late the version of the technology they wish to consider.While the ambiguity in definitions of NIPT requires extrathought and contextualization, this ambiguity about howNIPT could or should be used also creates an opportunityfor ethical analysis to inform policy and regulation. At thispoint in time, potential uses of NIPT are still being con-structed, and there is room for flexibility before this tech-nology becomes stabilized in a narrower range of uses(Pinch and Bijker 1987). Ethicists working in this area mayfind it useful to clearly articulate the version of NIPT theyare considering, for instance, by making note of theassumptions they are making about the technology (Bennand Chapman 2009) or considering how ethical issues maychange with different deployments of the technology(Deans and Newson 2012).

Limitations

This article considered the versions of NIPT as constructedby two types of organizations that claim authority to createa version of this technology: vendors and health care pro-vider organizations. Future research may wish to examinehow other groups construct NIPT, potentially sheddinglight on which versions of the technology have gained trac-tion in different circles or become picked up in popularusage. Further examination of this type of patient educa-tion document may include consideration of how the con-ditions tested for are portrayed and the potentialdirectiveness or nondirectiveness toward a particularaction (i.e., testing, termination upon positive result)implicit in that portrayal, similar to work that has beendone with patient information pamphlets for other typesof prenatal screening (Lawson, Carlson, and Shynkaruk2012; Vanstone and Kinsella 2010).

While this article examines the way that NIPT is cur-rently constructed by vendors and professional societies, itis important to appreciate that technologies change overtime and NIPT seems likely to change more quickly thanmost, given the number of new applications currently indevelopment (Gonzalez�Gonzalez et al. 2002; Hill et al.2012; Li et al. 2007; Nasis et al. 2004 Saito et al. 2000; Sakeret al. 2006). For example, two teams have now sequencedan entire human genome from fetal cells. Soon, any geneticcondition or trait could be identified by NIPT (Fan et al.2012; Hui and Bianchi 2013).

CONCLUSION

In this article we have argued that NIPT is not one technol-ogy, but several technologies that use a similar analyticprocess to provide information about cell-free DNA. Thesetechnologies differ in terms of proposed purpose, relation-ship to other technologies, target population, and condi-tions tested for. The various conceptions of NIPT entaildifferent ethical implications. Contextualizing a particularversion of NIPT technology for ethical analysis requires aconsideration of how the technology will be used in prac-tice, including the purpose, relationship to other technolo-gies, target population, screening or diagnosticcapabilities, fallibility, target conditions, related risk, out-comes, available interventions, and related health care pro-viders. We encourage those conducting ethical analyses ofNIPT to be specific and particular about what kind ofNIPT they are considering.

AUTHOR CONTRIBUTIONS

All authors contributed to the conception and design ofthis study. Data collection was performed by MV andKY. All authors participated in data analysis. The articlewas drafted by MV. All authors reviewed the article,

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provided critical feedback, and approved the submittedversion.

FUNDING

This work was funded by the Ontario Ministry of Healthand Long-Term Care through a Health System ResearchFund grant entitled “Harnessing Evidence and Values forHealth System Excellence.” The views expressed in thearticle are the views of the authors and should not be takento represent the views of the Ontario Ministry of Healthand Long-Term Care.

CONFLICTS OF INTEREST

The authors report that they have no conflicts of intereststo declare.

ETHICAL APPROVAL

Because the data used for this study were publicly avail-able, research ethics approval for this study was notnecessary. &

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