Medicine, Faculty of
Non UBC
Pathology and Laboratory Medicine, Department of
DSpace
Healthcare 10 (10): 2086 (2022)
Provincial Health Services Authority (B.C.)
Husereau, Don
Steuten, Lotte
Muthu, Vivek
Thomas, David M.
Spinner, Daryl S.
Ivany, Craig
Mengel, Michael
Sheffield, Brandon
Yip, Stephen
Jacobs, Philip
Sullivan, Terrence
Health systems internationally must prepare for a future of genetic/genomic testing to inform healthcare decision-making while creating research opportunities. High functioning testing services will require additional considerations and health system conditions beyond traditional diagnostic testing. Based on a literature review of good practices, key informant interviews, and expert discussion, this article attempts to synthesize what conditions are necessary, and what good practice may look like. It is intended to aid policymakers and others designing future systems of genome-based care and care prevention. These conditions include creating communities of practice and healthcare system networks; resource planning; across-region informatics; having a clear entry/exit point for innovation; evaluative function(s); concentrated or coordinated service models; mechanisms for awareness and care navigation; integrating innovation and healthcare delivery functions; and revisiting approaches to financing, education and training, regulation, and data privacy and security. The list of conditions we propose was developed with an emphasis on describing conditions that would be applicable to any healthcare system, regardless of capacity, organizational structure, financing, population characteristics, standardization of care processes, or underlying culture.
Citation: Husereau, D.; Steuten, L.;Muthu, V.; Thomas, D.M.; Spinner,D.S.; Ivany, C.; Mengel, M.; Sheffield,B.; Yip, S.; Jacobs, P.; et al. Effectiveand Efficient Delivery ofGenome-Based Testing-WhatConditions Are Necessary for HealthSystem Readiness?. Healthcare 2022,10, 2086. https://doi.org/10.3390/healthcare10102086Academic Editor: Simona ZaamiReceived: 22 August 2022Accepted: 12 October 2022Published: 19 October 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).healthcarePerspectiveEffective and Efficient Delivery of Genome-Based Testing-WhatConditions Are Necessary for Health System Readiness?Don Husereau 1,* , Lotte Steuten 2,3, Vivek Muthu 4, David M. Thomas 5,6, Daryl S. Spinner 7, Craig Ivany 8,Michael Mengel 9 , Brandon Sheffield 10, Stephen Yip 11, Philip Jacobs 12 and Terrence Sullivan 13,141 School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON K1G 5Z3, Canada2 Office of Health Economics, London SE1 2HB, UK3 City Health Economics Centre (CHEC), City University of London, London EC1V 0HB, UK4 Marivek Healthcare Consulting, Epsom KT18 7PF, UK5 Garvan Institute of Medical Research, Sydney, NSW 2010, Australia6 Omico, Sydney, NSW 2010, Australia7 Menarini Silicon Biosystems Inc., Huntingdon Valley, PA 19006, USA8 Provincial Health Services Authority, Vancouver, BC V5Z 1G1, Canada9 Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada10 William Osler Health System, Brampton, ON L6R 3J7, Canada11 Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia,Vancouver, BC V6T 1Z7, Canada12 Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada13 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON M5T 3M6, Canada14 Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada* Correspondence: donh@donhusereau.com; Tel.: +1-6132994379Abstract: Health systems internationally must prepare for a future of genetic/genomic testing toinform healthcare decision-making while creating research opportunities. High functioning testingservices will require additional considerations and health system conditions beyond traditionaldiagnostic testing. Based on a literature review of good practices, key informant interviews, andexpert discussion, this article attempts to synthesize what conditions are necessary, and what goodpractice may look like. It is intended to aid policymakers and others designing future systemsof genome-based care and care prevention. These conditions include creating communities ofpractice and healthcare system networks; resource planning; across-region informatics; having aclear entry/exit point for innovation; evaluative function(s); concentrated or coordinated servicemodels; mechanisms for awareness and care navigation; integrating innovation and healthcaredelivery functions; and revisiting approaches to financing, education and training, regulation, anddata privacy and security. The list of conditions we propose was developed with an emphasis ondescribing conditions that would be applicable to any healthcare system, regardless of capacity,organizational structure, financing, population characteristics, standardization of care processes, orunderlying culture.Keywords: diagnostic molecular pathology; genetic testing; diagnostic services; technology assess-ment; biomedical; genetic services; financial support; clinical governance; health technology; healthcare innovation1. IntroductionClinical decisions are increasingly informed by biomarker-defined subsets of patients,forming the basis of precision medicine. The measurement of laboratory-based biomarkersmay serve one or more purposes for patients and healthcare providers—including iden-tifying who has disease or may develop future disease, monitoring health, monitoringresponse(s) to therapy, predicting who may most benefit or be harmed by therapy, orpredicting how disease is likely to progress [1]. Increasingly, advanced tests are being used.Healthcare 2022, 10, 2086. https://doi.org/10.3390/healthcare10102086 https://www.mdpi.com/journal/healthcareHealthcare 2022, 10, 2086 2 of 17These involve measures of the expression, function and regulation of genes through a directexamination of genes (through cytogenetics or various genomic tools), or their proteinproducts (for example by immunohistochemistry). These techniques have already becomea hallmark of decision-making in oncology, given cancer is a genetic disease and may beamenable to targeted therapy. They are also increasingly playing a role in the identificationof disease, with comprehensive genomic testing approaches demonstrating much higherdiagnostic yields than conventional approaches. A prospective study of 103 children withsuspected underlying genetic disorders led to 18 new diagnoses of disease when usingwhole-genome sequencing compared to conventional approaches to diagnosis (i.e., targetedgene sequencing) [2].In this rapidly developing field, healthcare system administrators are faced withdecisions regarding what biomarkers and technologies to adopt. These include differ-ent technical platforms (e.g., single-gene, multi-gene, whole-exome, and whole-genomesequencing and expression analysis); modalities (tissue, saliva, blood, or urine-based sam-pling); location (laboratory-based or delivered at point-of-care); provenance (commerciallyavailable in vitro diagnostic tests and services versus in-house/laboratory developed tests);and timing and sequencing of tests. All of these factors affect clinical utility, includingcosts and patient outcomes, and broader health system goals such as caregiver and patientexperiences. They will also influence how care is delivered.Realising benefits from genome-based testing requires expenditure on equipment,reagents and informatic tools for their mainstream delivery, and creates added challengesfor healthcare systems and their stewards. These challenges include, but are not limited to:management costs associated with development of new protocols, implementation, valida-tion and licensing; the need to revisit clinical and referral pathways, scopes of practice, andcare protocols; the need to revisit use of associated resources, including upstream tissuesampling and downstream use of targeted therapies; the need to define minimally accept-able technical standards to allow for collection of samples; the need to revisit associatedhuman resource requirements, such as laboratory technologists/technicians, bioinformati-cians, clinical geneticists, and genetic counsellors; enhanced data systems in evaluationand reporting, that also consider privacy and security. These challenges combined speak toa need to revisit historical models of technology management, including the governance,administration, and financing of laboratory services.Unlike traditional healthcare technologies, genome-based biomarker testing also pro-vides research opportunities beyond healthcare decision making, and may lead to discov-eries about the nature of disease or effectiveness of current and future therapies. Theseopportunities are being developed in ‘real time’, within routine clinical use, thus blurringthe boundaries between research and standard practice. For example, tests may qualifypatients for clinical trials, which has important clinical, scientific and economic benefits [3].The value of integrating research into clinical practice was underlined during the COVID-19pandemic, where rapid research-led development and implementation of testing capacitywas essential for both monitoring the pandemic, and the development of preventive andtherapeutic strategies. Yet, the value of research in healthcare is not integrated into healthtechnology assessment in most single payer systems [4].Given the potential for exponential growth of new tests and test approaches, andthe complexity of introducing them, health system planners preparing for a future ofgenome-based biomarker testing need to grapple with how these services can be deliveredeffectively and efficiently. As the structure, remit and organization of healthcare systems(and the laboratory functions within them) vary, there are likely to be no one-size-fits-allsolution; however, some necessary conditions will be required to manage these technologiesin a way that benefits patients and is sustainable.The purpose of this report is to describe the conditions necessary for policymak-ers and health system planners to enable a state-of-the-art testing service that includesgenome-based testing for acquired and heritable diseases as well as risk assessment tosupport preventive and public health interventions. The list of conditions we propose wasHealthcare 2022, 10, 2086 3 of 17developed with an emphasis on describing conditions that would be applicable to anyhealthcare system, regardless of capacity, organizational structure, financing, populationcharacteristics, standardization of care processes, or underlying culture [5].2. Materials and MethodsThe conditions identified in this report were developed through a mixed-methodsapproach. A narrative literature review was conducted based on a purposive sample ofcommercially published and grey literature. Searches (See Supplementary Materials forsearch strategy) were performed by a medical librarian specialist and relevant informationwas identified by a single reviewer (DH). In parallel, conditions were identified using aconventional content approach and based on semi-structured interviews (n = 18; 30–60 min)with key informants and performed from a constructivist point of view. All interviewswere conducted by DH with a purposive sample of experts including several of the authors(VM, DMT, DSS, CI, MM, BSS) as well as representatives from pharmaceutical (n = 6) anddiagnostic (n = 1) companies. Informants were chosen based on differing expertise andgeographic location with some (n = 4) having previously worked with the author.Interviews were conducted via a recorded video conference call using an interviewguide, and all participants approached agreed to be interviewed. Summary notes fromtranscripts were shared back with participants for verification (member checking). Aninformal identification of concepts was conducted by one author (DH), and categorizedinto themes/conditions.A preliminary list of conditions identified through interview and the literature reviewwas then circulated back to all authors for feedback and a moderated face-to-face discussion.“Effective and efficient” delivery of genome-based diagnostics from testing was definedas one that would most satisfy the “quadruple aim” of reducing per capita costs whileimproving population health outcomes, patient and caregiver experiences, and providerexperiences [6]. These conditions are explained, and grouped according to these aims, andwith examples in the next section.3. ResultsInterviewees (Table 1) described a number of challenges in achieving the quadrupleaim of healthcare within current approached to the implementation and managementof genomic testing. These largely related to care interruptions or wait times due to anumber of underlying factors (resources and finance planning; education; informatics;and an unclear process for onboarding tests). Other challenges included inappropriateidentification of patients and family members; inequitable care delivery; uncoordinated,inconsistent, inappropriate or duplicative care; and inefficient, low-value care. These aregrouped by theme in Table 2.Table 1. Interviewee characteristics.Participants (n = 18) N, (%)Female 6 (33)Primary rolePhysician/lab leader 4 (22)Health care administrator 2 (11)Health services expert/health economist 4 (22)Patient representative 1 (6)Private sector representative 7 (39)Work environmentPublic sector 11(61)Private sector 7 (39)LocationCanada 14 (78)United States 2 (11)Europe 1 (6)Other 1 (6)Healthcare 2022, 10, 2086 4 of 17Table 2. Thematic analysis of challenges identified along with corresponding enabling conditions.Quadruple AimDomain * Challenge/Theme Identified Key Informant QuotePotential Solution/Condition(s)to Help AddressWork life of careprovidersCare interruptions and waittimes“It is a challenge to connectdifferent streams of planning. Animble lab service is highlydependent on integrated labsystems and capital planning.Workforce planning and educationis also critical”“There is a need to triage theurgency based on the testapplication and clarity about theprerequisite level of evidence toapply”• Resource planning• Financing approach• Education and training• Informatics• Evaluative function• Entry/exit point for innovationPatient and caregiverexperiencesInappropriate identification ofpatients and family members“There is a need for standardsaround governance, security andpatient consent, what we can usethe data for etc. Rule aroundcommercial interests in data need tobe in place [as well as] someconsideration of investing in thelaboratory function independentlyof therapeutic application”• Service models• Awareness and care navigationInequitable care delivery“Legislation plays an important roleas well. The Acts give differentprovinces different levels ofinfluence over care coordination”• RegulationHealth ofpopulationsUncoordinated, inconsistent,inappropriate or duplicativecare“There is a need to have clearunderstanding of what the carepathway is and an alignedcommunity of practice”• Integration of innovation andhealthcare delivery• Creating communities ofpractice and healthcare systemnetworksPer capita costs ofhealthcare Inefficient, low-value care“So then we invest in standards,outcome measures, qualitymeasures etc. along with a process.You can’t be too prescriptivebecause of the wide utility oftesting”“Information is also valuable andmust be valued. Currentlyinformation is generated formedico-legal purposes and yet itcould be generated to generaterevenue and lower care costs”• Integration of innovation andhealthcare delivery* Challenges and themes span across some quadruple aim domains, so rows are deliberately misaligned.From the challenges identified, an initial list of 14 conditions were identified and pareddown to 12. These conditions for testing have been characterized as being part of infrastruc-ture and planning; operations; or the general, health care environment. The sections belowprovide further elaboration of these, with examples. A summary of conditions, along witha description of issues they are intended to address, and the goals and description of goodpractice are in Table 3.Healthcare 2022, 10, 2086 5 of 17Table 3. Enabling conditions for state-of-the-art delivery of genome-based testing.Issue Goal Description of GoodPractice Policy ExampleInfrastructureCreating communities ofpractice and healthcaresystem networksInequitable caredelivery Broad stakeholderagreement onappropriate use Equitable care Engagement across allstakeholdersThe Australian Genomics HealthAlliance, for example, is anattempt to accelerate andevaluate the application ofgenomic testing in healthcare. Itis a “collaborative researchpartnership across more than80 diagnostic laboratories,clinical genetics services, andresearch and academicinstitutions” [7].Resource planningCare interruptions,wait times orunsustainable care Sustainable caredelivery Frequent (e.g.,1–3 years)reassessment Available to allhealthcarestakeholdersThe US GovernmentAccountability Office conducteda study forecasting a futureshortfall of genetic counsellorsand medical geneticists ingeneral, and by geographicregion [8].InformaticsUncoordinated orduplicative care,inconsistent testdevelopment, poorinformation forevaluation Care coordination Scientific insight–clinical discoveryand health systemperformance Across-regionintegration Lab informationintegrated withelectronic healthrecord and healthcareevaluation functionThe UK Department of Health &Social Care committed “£4billion over a five-year period(2016-21) in digital technology,systems and infrastructure, toprovide the health and caresystem with the digital capabilityand capacity it needs . . . .” [9].OperationsEntry/exit point forinnovationTechnology creepand poorlyperforming legacytechnology Appropriate healthtechnologymanagement Open application andevaluation process Proposals acceptedfrom all stakeholders Explicit timelines Reassessment processNHS England, has announced itsdecision to revisit tests annually,and considering the co-ordinatedreplacement of older tests withnew and emerging approaches,including considering whereevidence still needs to becollected to validate the benefitof moving to [whole-genomesequencing], and identifyingwhere alternative genomicdiagnostics, such as gene panelsor microarrays, will continue tobe needed [9].Evaluative Function Avoid low valuecare Legitimacy indecision-making Clear signal forinnovators Adherence to keyprinciples in healthtechnologyassessment includingtransparency,timeliness andstakeholderengagement [10] Consistent evaluativeframeworkAn evaluative framework forgenetic testing developed for theUS Department of Defenserecognized the practical need totriage adoption decisions basedlevel on urgency through the useof rapid review and real-worldevaluation of new tests [11].Service models Inequitable andinefficient care Care coordination  Across-regioncoordinationNHS England GenomicLaboratory Hubs [12] and USDepartment of Veteran’s Affairsdedicated service centres fortesting [13].Awareness and carenavigationConfusion or lack ofinformationregarding testavailability Access to care Available, up-to-dateinformation of testavailability and howto access Additional supportsfor care navigationIn France, where testing is morevariable across regions, lists ofdifferent laboratory sites withcontact information are provided[14].Healthcare 2022, 10, 2086 6 of 17Table 3. Cont.Issue Goal Description of GoodPractice Policy ExampleHealthcare EnvironmentIntegration ofInnovation andHealthcare DeliveryCare lagging behindpace of careinnovation andscientific advances Maximize carevalue Private public sectorpartnerships, and/or Integration ofinvestigational andestablishedtechnologyUK and Australianprivate-public-sectorpartnerships [15,16]. In Ontario,Canada, reflex testing for newlydiagnosed cases of NSCLC(adenocarcinoma/non-squamous) uses a panelconsisting of established andinvestigational biomarkers [17]Financing approachCare interruptions,wait times orunsustainable care Maximize carevalue Access to care Sustainable caredelivery Funds available onceadoption decisionmade Clear value-based,funding formula,amenable toreassessment Funding for testdevelopment,additional humanresource costsconsideredThe US Centers for Medicareand Medicaid Services (CMS)have attempted to incentivizemolecular diagnostic innovationby enabling manufacturer-setfree pricing for FDA-cleared orapproved tests under certainconditions [18].Education and TrainingInappropriate care;medical error; carelagging behind paceof care innovation High qualityworkforce and caredelivery Training thataddresses continuingprofessionaldevelopment,knowledge transferand qualityimprovement Across-regioneducational standardsThe Genomics EducationProgramme (GEP) in Englandplans to develop “genomiccompetencies for specialtytraining”, human resourceplanning, and providingsupports for “curriculadevelopment and medicalrevalidatio” [9].RegulationSubstandard care ,negligence and legalliability Minimizepreventable harm toindividuals frompoor test quality Regulation thataddresses humanresource qualificationsand training,documentation ofrecords, qualitycontrol processes, andproficiency testing[19–21]. Across-region analyticstandardsRegulation is typicallyaddressed through accreditationprocesses that conform with theInternational Organization forStandardization (ISO) includingISO 15189 Medical Laboratories.Examples include regulation ofclinical genetic testing throughCLIA in the US and CanadaData privacy andsecurityInappropriateidentification ofpatients and familymembers Minimizepreventable harm toindividuals andfamilies from testing Framework thataddresses privacy andsecurity concernsfrom genetic testing Across-region privacystandardsThe Global Alliance forGenomics & Health, has createda Framework and “CoreElements for Responsible DataSharing” [22].3.1. Infrastructure and Planning3.1.1. Creating Communities of Practice and Healthcare System NetworksA well-established network can serve as a basis for deliberation about what tests musthave priority, how tests may be valued, what care standards should be in place, whatresources will be necessary, how care can be monitored, and other necessary collectivejudgements that may vary geographically and over time. There will also need to be broadagreement on the use of shared resources, such as biobanks and reporting standards.In regions with more dispersed delivery of care, efforts to create networks may requiretiering: first, there is a need to establish across-region consortia to establish wider carestandards, shared informational resources, educational standards, and ensure the equitabledelivery of services [23]; secondly, there is a need to create strong intraregional consortiafor fully integrated delivery of services (i.e., local communities of practice or “collaborativecommunities” [24]).Healthcare 2022, 10, 2086 7 of 17Testing is a complex intervention [25] that relies on the timing, expertise, and behaviouracross multiple stakeholders for its effective delivery. At its core is a community of practicethat includes laboratory leaders and healthcare providers who will have the greatestimpact on multidisciplinary decisions in regards to testing, including how and underwhat conditions a test should be delivered [26]. Broader members of the communityare those who will be impacted by the consideration and implementation of new testing.These include the patients, administrators, IT professionals, implementation and genomescientists, public and private sector innovators and others (scientists, legal and ethicsexperts, professional organizations, bioethicists, regulators). As these groups may not beconnected through an organizational structure, strong networks with clear communicationbetween individuals and programs are required for effective implementation and gooddecision-making [24].Many international jurisdictions have already established networks through transla-tional research initiatives [27]. In pluralistic or federated health systems such as Swedenand Canada there has been an emphasis on “bottom-up” approaches to creating regionalcapacity that foster the building up of self-selected organizations aligned with a core set ofgoals. Some federated jurisdictions, such as Australia, have taken a further “top-down”approach to creating networks after mapping jurisdiction-wide capacity. The AustralianGenomics Health Alliance, for example, is an attempt to accelerate and evaluate the appli-cation of genomic testing in healthcare. It is a “collaborative research partnership acrossmore than 80 diagnostic laboratories, clinical genetics services, and research and academicinstitutions” [7].In more centralized healthcare systems such as England’s National Health Service(NHS England), where higher level coordination already exists, the emphasis has been onregional care coordination. Collaboration in England has been facilitated by creating theNHS England Genomic Medicine Service Alliance, an effort to bring together GenomicLaboratory Hubs together with “clinical genetic services inclusive of genomic counsellors,provider organisations across the care continiuum [sic] and with Primary Care Networks,Cancer Alliances, research and academia and patients and public representatives” [28]. Inparallel, a consortium of academic researchers (a community of approved researchers withaccess to the Genomics England Research Environment) was also created as a mechanismof reaping benefits from scientific spillovers from genomic information.3.1.2. Resource PlanningResource management and planning for expected impacts on time, people, facilities,equipment, supplies, and information technology is an essential activity in any healthsystem. However, the rapid rate of change of underlying technology and the need forspecialized human resources including those involved in tissue sampling (e.g., biopsy),analysis (laboratory technologists/technicians, bioinformatic) and post-test counselling(counsellors and other specialized training) necessitates long-term capital and human re-source planning. Workforce planning will need to consider the training and credentiallingof highly specialized resources involved with testing. It may also need to consider a plausi-ble range of scenarios of what services are required and the roles and responsibilities ofthose involved [29,30]. For example, the US Government Accountability Office conducted astudy forecasting a future shortfall of genetic counsellors and medical geneticists in general,and by geographic region [8]. Advances in searchable genomic databases to support clinicalmanagement, alternative models of service delivery, and centralized delivery of servicescould greatly reduce the need for these highly specialized human resource requirements incoming years [23,31,32].Resource planning for the coming era of genomic medicine will require health systemplanners to revisit traditional funding formulas. Laboratory funding based on volumeor a “per-test” approach may not incent its use as it ignores efficiencies that could berealized with changes in approach to testing type (e.g., multigene assay versus singlegene approaches [33]), modality (e.g., reflex testing or upfront testing versus orderedHealthcare 2022, 10, 2086 8 of 17testing or sequential testing [34]) or test timing [35,36]. Additional bioinformatics andtechnologist/technician resources also require consideration. In the UK, for example, theDepartment of Health & Social Care committed “£4 billion over a five-year period (2016–21)in digital technology, systems and infrastructure, to provide the health and care systemwith the digital capability and capacity it needs . . . .” [9].3.1.3. InformaticsTraditionally, laboratory information management emphasizes informatics as a toolfor sample tracking and communicating results. For genome-based testing, informaticsis also essential for test development, interpretation, and clinical decision support [37,38].Ensuring adequate integration of test results into electronic health records will also providea key resource for real-world monitoring, disease management, quality assessment andassurance, and financing [39]. Integration of laboratory information systems with electronichealth record systems is also needed to reduce duplication of testing and as a basis for carecoordination across health professionals or organizations. An increasingly important aspectof genome-based testing is the ability not only to share information within a healthcaresystem, but also to share and access data from other informational sources, includingexternal databases, peer-reviewed literature and other healthcare systems.Histopathology represents a major portion of laboratory medicine and involves im-ages interpreted by human physicians. This area has existed for over a century as anunquantifiable practice within medicine. In the current digital era, digitization of stainedimages represents a major advance in the practice of personalized medicine. As infor-matics capability continues to expand, health systems may plan for the integration ofdigital histomorphologic data and its ongoing analysis into genomics and personalizedmedicine [40].3.2. Operations3.2.1. Entry/Exit Point for InnovationThe rate of proposals for new tests and testing modalities necessitates a clear processfor the managed adoption and obsolescence of tests [41]. A single point of entry forconsidering new tests using an application procedure coupled with an evaluation processand formulary is one increasingly used approach that allows multiple stakeholders toengage with the healthcare system [42]. It can also reduce unnecessary testing whileproviding a strong signal to public and private sector innovators regarding when andunder what conditions tests will be adopted [43]. This approach is used in the Canadianprovinces of Alberta and Quebec, where an intake form requesting a new test (councils,strategic clinical networks, physicians, patients, innovators or the public) will lead to anevidence-assessment and recommendation before a test is placed on a public formulary.Given the rate of technologic development, healthcare systems will also need tograpple with timeliness, i.e., how long to adopt tests and when tests should be reassessed.New test adoption is a healthcare challenge, as many tests must be considered in thecontext of other interventions, such as their use as companion diagnostics for new drugs.Any decision to replace or revise an existing test, such as expanding a multigene panel,must consider the balance between patient and healthcare provider unmet need with theinevitable disruption to care protocols, and the speed at which new tests can be replaced.NHS England, for example, has announced its decision to revisit tests annually, andconsidering the coordinated replacement of older tests with new and emerging approaches,including considering where evidence still needs to be collected to validate the benefitof moving to [whole-genome sequencing], and identifying where alternative genomicdiagnostics, such as gene panels or microarrays, will continue to be needed [9].3.2.2. Evaluative FunctionMany health systems worldwide have adopted evaluation frameworks for testingbased on the analytic validity, clinical validity, clinical utility, and ethical, legal, and socialHealthcare 2022, 10, 2086 9 of 17implications (ACCE) approach [44]. While this can be seen as a starting point for evaluationof tests from a clinical standpoint, the ACCE approach does not consider “context-relatedevaluation dimensions (delivery models, economic evaluation, and organizational aspects)”that will be of interest to policymaking and are a standard part of health technologyassessment (HTA) processes [45]. Even using the ACCE framework, it has been arguedthat ‘clinical utility’ is poorly defined; definitions “may focus on a test’s ability to producea diagnosis, broader definitions of clinical utility consider health and non-health related,familial and societal outcomes”. Expanded notions of utility, that consider the wider impactof a test result on not only the individual patient, but their families and broader society,may be required to capture benefits to society [46,47].Many issues related to testing, including availability of evidence and context-drivenperformance are part of a broader suite of limitations faced by administrators when eval-uating diagnostic tests and medical devices [48]. As such, the timing and complexity oftraditional approaches to HTA must be balanced against patient need, in an environmentwhere test utility and cost is dynamic. Literature-based approaches to estimating test utilitymay be limited by enhancements to technology, learning curves [49] or implementationcharacteristics that affect performance [50]. This strongly suggests the recommended use ofboth pre-market and post-market data to capture impact of learning curve on outcomes [4]as well as a consideration of costs of implementation when assessing value [51]. Further-more, and in keeping with key principles for HTA [10], decisions regarding access to testingmust be made in a timely manner. Both of these issues are addressed in an evaluativeframework for genetic testing developed for the US Department of Defense which recog-nized the practical need to triage adoption decisions based level on urgency through theuse of rapid review and real-world evaluation of new tests [11].Traditional assumptions and approaches underlying the economic evaluation of deci-sions for drugs are also challenging to apply [52]. These include the constancy of marginalbenefits and costs, and the divisibility of tests provided [53,54]. Payers should expectthe marginal costs of adding new tests to a panel or going to a whole exome or genomeapproach to be quite small relative to other factors such as patient selection, level and typeof implementation (education of providers, equipment, geographic distribution) as well asdownstream costs (e.g., use of targeted therapies) [55].3.2.3. Service ModelsLike many other forms of production, good practices in organizing health servicesneeds to consider the degree to which the configuration of delivery is concentrated ordispersed. Dispersed arrangements are more attractive when unit costs do not benefitfrom economies of scale—such as with primary care and community pharmacy services—and coupled with the need for geographic reach [30,32]. In contrast, economies of scalefrom advanced testing, coupled with the need for a high degree of standardization andaccountability suggest genome-based testing will benefit from a more concentrated modelof service delivery.A further consideration will be to what degree a more concentrated model can bedelivered. Service models must first consider care pathways and requisition authority fortesting. Models include requisitions by geneticists, primary care practitioners, medicalspecialists, program-based (such as newborn screening) or direct-to-patient and will dependon the purpose of testing [56]. Genetic testing may be required by independent healthcareprograms that are uniquely organized, such as prenatal, pediatric, infectious disease,psychiatry, primary care, and oncology. In some cases, a single test (e.g., BRCA) may beused to assess future risk of disease, prognosis of disease, or predict response to treatmentcould have different clinical applications, referral pathways, and healthcare system value.Point-of-care testing (POC) technology is also increasingly available, which can ex-pedite decision-making but also challenges a more centralized model of care, and thestandardization and accountability that comes with it. POC devices do not negate theneed for quality control, external quality assessment, provider training, and data sharingHealthcare 2022, 10, 2086 10 of 17associated with testing. POC tests also further highlight the need for technology adoptiondecisions that consider an entire community of practice—differences in speed of test resultsand analytic characteristics will have a downstream impact on patient and healthcareprovider experiences.Care coordination may be greatly facilitated by already-centralized healthcare envi-ronments. The NHS England was able to reorganize its existing capacity in 2018, creatinga Genomic Medicine Service through its Genomic Laboratory Hubs, each hosted by anacute NHS trust and designated a geographic region for coverage [12]. Similarly, theUS Department of Veteran’s Affairs has leveraged its existing capacity to deliver genetictesting through its oncology program and dedicated service centres across the US towardnon-oncologic indications for testing [13].In pluralistic or market-based healthcare systems, coordination of care across disparateorganizations is facilitated through the use of care standards linked to incentives. Israel,for example, has decided to create regional capacity to deliver comprehensive genomicprofiling for non-small cell lung cancer by allowing its separate health management or-ganizations (Kupot Holim) to use their own validated testing approaches, in accordancewith specific conditions. Spain, has similarly provided overarching guidance to its au-tonomous health regions regarding the principles that underly the delivery of genetictests [57]. Even when designed with best intentions, these approaches may still lead toregional variation and concerns regarding inequity of access. The Spanish Minister ofHealth has recently announced further efforts will be made to make country-wide access totesting more consistent [58].3.2.4. Awareness and Care NavigationEven with necessary test infrastructure and accessibility, healthcare systems mustconsider how to communicate to patients and healthcare providers what tests are availableand to who and how these are paid for. Published test formularies are a starting point forcommunicating what tests are available and how they can be accessed. In the Canadianprovince of Alberta, the addition of tests to a formulary had a stated goal of “streamlin-ing processes by reducing variation in testing and improving healthcare provider andpatient access to appropriate, equitable and sustainable laboratory test information [59]”. Incountries with pluralistic healthcare systems and lacking a common directory, other infor-mation can be provided to help care navigation. In France, where testing is more variableacross regions, lists of different laboratory sites with contact information are provided [14].Similarly, the US NIH has developed a test registry, which “contains information aboutlaboratories and the tests they offer but does not contain or gather information on genetictest results” [60].3.3. Healthcare Environment3.3.1. Integration of Innovation and Healthcare Delivery FunctionsGiven the rapid future pace of the introduction of new tests, coupled with the potentialresearch benefits associated with testing, healthcare systems will need to consider howthe delivery of testing or scientific discovery alongside testing for healthcare decision-making will be coordinated. This is an inherent challenge with exome- or genome-widesequencing, which will invariably reveal genetic variants of strong therapeutic, prognostic,or diagnostic significance alongside those lacking evidence [61]. Investigational tests canplay an important role in patient care: qualifying patients for clinical trial enrollment, as wellas other research endeavors that further understanding of disease. European guidelineshave addressed this by suggesting the distinction is clear when reporting results [26].In Ontario, Canada, for example, reflex testing for newly diagnosed cases of NSCLC(adenocarcinoma/non-squamous) is performed using a panel consisting of more well-established biomarkers. Targeted treatments are currently available for some of the genestested (e.g., EGFR, ALK, KRAS), but not for others (e.g., FGFR1, SMARCA4, PIK3CA) [17].Healthcare 2022, 10, 2086 11 of 17Funding tests for “targetable” and “non-targetable” genes together is a pragmaticsolution, and is also facilitated by massive parallel (“next-generation”) sequencing whereadditional tests can be added to an assay at negligible cost. It can also allow health systemsto revisit testing regimes with less frequency, and avoid significant change managementcosts. In practice, however, funding both “medically necessary” and “investigational”testing can create a significant conflict for existing insurer frameworks that use evidence andclinical consensus to determine what biomarkers should be funded [62,63]. This challengeled one commentator to ask: “do we redefine [testing] to fit the coverage and evidenceframework, or do we redefine the coverage and evidence framework to fit [testing] [63]?”Proposals to change coverage frameworks have been well described and are intendedto address payer risk through performance-based payment or coverage with evidence de-velopment [63,64]. While a step forward, these solutions may still be difficult to implementin practice, given the inherent limitations of using real-world data to establish the clinicalutility of testing [65]. Approaches to circumventing evidence challenges include the use ofstandardized outcome measures, cascade testing and data sharing through internationalconsortia [66].A separate solution is to create translational research programs that work in parallelwith health systems, or ideally are fully embedded within learning healthcare systems [66].Many of these already exist today, often facilitated through public-private sector partner-ships, the majority intended to investigate normal genomic variation by sequencing healthyparticipants (i.e., biobanking) [27]. Some also have stated aims of drug discovery and inte-grating well-established and emerging tests into regular healthcare system delivery. TheAustralian government, for example, has created unique partnerships between government,industry, and academia to conduct clinical trials to establish the clinical utility of compre-hensive genomic profiling in lung cancer [15], as well as a more recent announcement forrare disease [16].3.3.2. Financing ApproachThe anticipated rate of entry of new tests also requires a nimble financing approach,allowing funds to be released for new tests once decisions to reimburse are made. Thismay require a shift in thinking for many insurers, who have historically allocated fundingfor laboratory services on an annual basis based on test volumes [64]. Unlike traditionaltests, funding formulas for genetic testing must consider the need for additional humanresources associated with development and proficiency testing [67]. Payment models forcare may, in turn, drive laboratory utilization and require re-thinking [64,68].In the US, the Centers for Medicare and Medicaid Services (CMS) have attemptedto incentivize molecular diagnostic innovation by enabling manufacturer-set free pricingon the Medicare fee schedule for tests that meet specific Advanced Diagnostic LaboratoryTest (ADLT) criteria. Qualifying tests must be covered under Medicare, provided by asingle laboratory, and either (1) be FDA-cleared or approved, and/or (2) meet three specificcriteria ensuring molecular diagnostic innovation [18].Some insurers have also established funding for genetic biomarkers predicated ona “companion” diagnostic paradigm, releasing funds only when companion drugs areapproved. Genome-based biomarkers, however, are increasingly used for multiple drugs ortherapeutic decisions, including decisions not to use older drugs, and to shorten diagnosticodysseys for conditions with no specific drug therapies [69–72]. In some cases, jurisdictionshave additionally relied on pharmaceutical companies or public sector research grants tofund these one-drug, one-test dyads. For public insurers, this inevitably creates a situationwhere public sector actors are dependent on the private sector (or others) for the deliveryof public services, and yet public actors remain accountable to the public at large. This“private finance initiative” type of problem means testing health system priorities aredictated by who is paying, rather than unmet need, equity, or efficiency [73]. In addition tocreating structural inefficiency, these arrangements may be disruptive if funds are quicklywithdrawn: research grant funding may cease or move away with an investigator; or, aHealthcare 2022, 10, 2086 12 of 17drug company may change its external funding policies. The same company may alsoreasonably not want to pay for tests that aid competition.3.3.3. Education and TrainingGenetic testing through interprofessional teams distributed across centres and pro-grams introduces new challenges for educating healthcare professionals when creatingsystem-wide changes. Implementation new genome-based tests will change workflow, andnecessitates training at the intersection of continuing professional development, knowledgetransfer and quality improvement [32,49,74]. This in turn may require new approaches toteaching including workplace-based assessment and in situ simulation that address themany contextual requirements of testing that can change ultimately affect test performance,including “coordination of care, tissue procurement and handover, requisition and reportdesign, clear workflow within and between services, automatic information exchangebetween electronic health systems, and improved communication, with fast feedback loopsbetween health care practitioners [75]”.The need for a significant level of education caused by a significant disruption toorganization of services is reflected in the approach proposed by the Genomics EducationProgramme (GEP) in England. The Programme “routinely engages with the Medical RoyalColleges and actively participates in the NHS England and Academy of Medical RoyalColleges (AoMRC) Genomic Champions Group”. Among other areas of focus, the GEPplans to develop “genomic competencies for specialty training”, human resource planning,and providing supports for “curricula development and medical revalidation [9]”. Fundingfor each of the Genome Laboratory Hubs also considers the need for education and training.Some jurisdictions have even funded programs aimed at improving genomic knowledge inschool-aged children [76].3.3.4. RegulationWhile some health product regulators, such as the FDA, have begun to test claimsof clinical validity for commercially available tests, these do not address the multitude offactors that ultimately contribute to test utility and cost-effectiveness. This has heightenedthe need for effective systems of regulation to address the numerous factors that contributeto test quality, including human resource qualifications and training, documentation ofrecords, quality control processes, and proficiency testing [19–21]. Additional consider-ation must be given to the training, licensure, registration, and certification of geneticcounsellors [77].Most jurisdictions recognize that advancing the quality of testing requires regulatorystandards that involve multiple stakeholders, as it is widely recognized unwanted vari-ation in test performance is largely driven by steps taken before and after analysis [20].Regulation is typically addressed through accreditation processes that conform with theInternational Organization for Standardization (ISO) including ISO 15,189 Medical Labo-ratories. Examples include regulation of clinical genetic testing through CLIA in the USand Canada, and through the National Association of Testing Authorities and the RoyalCollege of Pathologists of Australia (NATA/RCPA) in Australia. In Europe, the CF Net-work, ERNDIM, GenQA (formally CEQA) and EMQN have more recently harmonizedaccreditation standards.3.3.5. Data Privacy and SecurityThe proper interpretation of disease-gene relationships, particularly for rare variants,require significant amounts of information including family histories and shared infor-mation across laboratories, both locally and internationally. The availability of partial orcomplete genomic information, however, may allow individuals to be identified. Testingalso raises ethical issues, such as the duty to warn first-degree relatives who may have ahigh chance of carrying a disease-causing gene [61]. As such, data requirements associatedHealthcare 2022, 10, 2086 13 of 17with genetic testing raise privacy and security concerns that may require revisiting ofhistorical legislation or policies.Some of these challenges may be overcome through the adoption of technical solutionsand data standards. Technical solutions include privacy-preserving solutions used ininformation systems, such as blockchain, to help avoid de-identification. Data sharingto community resources, such as the US National Library of Medicine’s ClinVar, is alsostrongly encouraged in international guidelines. Frameworks for data sharing have beenbolstered by international efforts, such as the Global Alliance for Genomics & Health, whichhas created a Framework and “Core Elements for Responsible Data Sharing” [22]. Theframework emphasizes maximizing data accessibility of data while minimizing harm topatients and others through a transparent and accountable system.Data privacy and security concerns may also be addressed through education andtraining (see Section 3.3.3). A core competency framework developed by NHS HealthEducation England, for example, identified six areas of proficiency for those responsible forcommunicating test results. A part of the framework addresses appropriate communicationof genomic results, including understanding “the implications of genomic testing forinsurance, including the UK Code on Genetic Testing and Insurance” [9].Some genetic tests may also require outsourcing, due to rarity or health system capacity.Genetic testing opens up the possibility of an output of unprocessed genetic data thatrequires interpretation from out-of-country providers. In these situations, health systemadministrators will also need to consider what information can or should lawfully beshared across borders.4. DiscussionOur effort to capture necessary conditions for state-of-the-art genome-based diagnos-tics service is intended to aid those who must design policies and processes intended tocapture the value of genome-based testing. While there is much focus on health technologyassessment (HTA) and economic evaluation as a policy response to new technology, wewould suggest appropriate management of health technology goes much further thanHTA [78]. The conditions listed here reflect broader conditions of high performing healthsystems that have been previously described [79–82]; these include the need to consider ac-creditation, regulation, provider training, care coordination, health information technology,evidence-based policy, and financing as a means to reduce inequity, improve care recipientand provider satisfaction, while moderating the rate of expenditure.While many of the conditions for optimal delivery of care could be applied to other dis-ruptive technologies, the key findings of our review suggest there are some conditions andgood practices that will be strongly emphasized in a high-performing genome-based testingservice. These include across-region informatics associated with testing, a framework thataddresses privacy and security concerns from genetic testing, as well as integration of aninnovation and healthcare delivery function through private public sector partnerships orthe sanctioned use of investigational technology in mainstream healthcare. Improvementsin these areas are significant challenges but necessary ones for a future of learning healthsystems [83].5. ConclusionsWe have identified 12 necessary conditions required for policymakers and health caresystem planners to achieve optimal experiences for care providers, patients and caregiverwhile achieving better outcomes and minimizing per capita health care costs in the comingera of genomic medicine. As these conditions have been identified through a comprehensiveliterature review and key informant interviews with international experts, they shouldbe applicable to any healthcare system, regardless of capacity, organizational structure,financing, population characteristics, standardization of care processes, or underlyingculture.Healthcare 2022, 10, 2086 14 of 17These conditions also reflect the multifaceted nature of laboratory technology man-agement as well as the need for additional considerations beyond traditional laboratorytechnology. As genome-based testing becomes more prevalent in coming years, we hopethese conditions and accompanying examples of good practice internationally provide someinitial guidance for those who will need to redesign healthcare systems to optimize care.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/healthcare10102086/s1, Supplementary Materials.Author Contributions: All authors (D.H., L.S., V.M., D.M.T., D.S.S., C.I., M.M., B.S., S.Y., P.J. andT.S.) contributed to the conceptualization, methodology, and writing—review and editing of thispaper and informed the list of conditions. D.H. was responsible for funding acquisition, and led thewriting—original draft. All authors approved the final version of the article. D.H. is the guarantor ofthis work. The corresponding author attests that all listed authors meet authorship criteria and thatno others meeting the criteria have been omitted. The conclusions of the authors were not contingenton the sponsor’s approval or censorship of the manuscript. The conclusions are the authors anddo not reflect the views of their affiliated organizations. All authors have read and agreed to thepublished version of the manuscript.Funding: Funding for this study was provided by: Amgen Canada, Inc.; AstraZeneca Canada Inc.;Eli Lilly Canada, Inc.; GSK Canada Inc.; Hoffmann-La Roche Canada, Inc. (Diagnostics Division);Janssen (J&J) Canada Inc.; Pfizer Canada Inc.; Thermo Fisher Scientific (Canada). All sponsorscontributed equally. None of the sponsors played a role in providing drafting, revising or approvingthe content of this research.Data Availability Statement: Not applicable.Acknowledgments: The authors would like to offer special thanks to the medical librarian specialist,Dagmara Chojecki, who led the development and execution of the electronic searches.Conflicts of Interest: The authors declare the following conflicts of interest. DH and LS reportfunding, outside the submitted work, from various pharmaceutical companies with an interest ingenome-based testing and precision medicine. DSS is a salaried employee of Menarini Silicon Biosys-tems, Inc. (Huntingdon Valley, Pennsylvania, USA) which is a commercial diagnostic manufacturer/clinical laboratory.VM advises a range of companies, including those with products and servicesrelated to the subject of this paper. Dr Muthu holds, and has held shares in health data, health ser-vices, healthcare consultancy and biotech companies, and serves or has served in paid non-executivedirector roles and paid advisory roles in such companies. The funders had no role in the design ofthe study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or inthe decision to publish the results.References1. Califf, R.M. Biomarker definitions and their applications. Exp. Biol. Med. 2018, 243, 213–221. [CrossRef] [PubMed]2. 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Effective and Efficient Delivery of Genome-Based Testing-What Conditions Are Necessary for Health System Readiness?
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