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Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions

Published:September 30, 2022DOI:https://doi.org/10.1016/j.gim.2022.09.004
      In the article “Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions” by Lavelle et al (Genet Med 2022;24:1349-1361), there were errors in Table 1 and Table 3 where the table footnote citations were incorrect. Please see the revised Table 1 and Table 3 shown below. The article has been corrected online and can be accessed at https://www.sciencedirect.com/science/article/pii/S1098360022006827?via%3Dihub.
      Table 1Select model parameters for base case and sensitivity analysis
      VariableBase CaseRange (min-max)
      Used in 1-way sensitivity analyses.
      Reference
      Probability of diagnosis following testing strategy
      Infants
       First tier SOC0.090.02-0.23Farnaes et al20, Willig et al21
       First tier trio ES0.370.28-0.43Used estimates from Lionel et al22 to adjust GS diagnostic rates to ES diagnostic rates
       First tier trio GS0.490.37-0.74Farnaes et al20, Willig et al21
      All children
       First tier trio SOC0.190.07-0.28Lionel et al22, Stavropoulos et al23
       First tier trio ES0.280.21-0.32Used estimates from reference Lionel et al22 to adjust GS diagnostic rates to ES diagnostic rates
       First tier trio GS0.370.28-0.51Lionel et al22, Stavropoulos et al23
      Testing costs
      Infants
       SOC (strategy A) testing before Dx$2154
      This cost was derived from the study by Shashi et al,24 which reported a charge of $3285 (2013 USD) for genetic testing performed on patients with suspected genetic conditions—who receive a diagnosis. This average charge included 41% of patients who incurred no charges ($0) for genetic testing because they were diagnosed by clinical criteria only, and 59% of the patients received testing at a charge of $5569 in 2013 USD. We converted this estimate of $5569 from charges to costs (using a cost-to-charge ratio of 0.33) and updated costs from 2013 to 2019 USD using the Consumer Price Index.
      $1077-$6462Shashi et al24
       SOC testing before ES/GS$2154
      This cost was derived from the study by Shashi et al,24 which reported a charge of $3285 (2013 USD) for genetic testing performed on patients with suspected genetic conditions—who receive a diagnosis. This average charge included 41% of patients who incurred no charges ($0) for genetic testing because they were diagnosed by clinical criteria only, and 59% of the patients received testing at a charge of $5569 in 2013 USD. We converted this estimate of $5569 from charges to costs (using a cost-to-charge ratio of 0.33) and updated costs from 2013 to 2019 USD using the Consumer Price Index.
      $1077-$6462Shashi et al24
       Diagnostic odyssey (SOC testing w/no Dx)$6566
      This cost is derived from the study by Dragojlovic et al,25 which estimated 10-year cost of the diagnostic odyssey for children with suspected genetic conditions. We included the cost estimates for diagnostic tests only. Costs were converted from 2016 CAD to 2019 USD. Future costs (years 2-10) were discounted to present value (year 1) costs using a 3% discount rate.
      $3283-$19,698Dragojlovic et al25
       ES trio rapid test$10,320$6720-$13,920Adjusted list prices
      All list prices were adjusted to expected CMS reimbursement rates using a ratio of 0.96. This ratio was derived by comparing mean list prices with 2019 Q4 CMS reimbursement rates for 3 tests for which we had both list prices and reimbursement rates: ES proband, GS proband, and GS trio.
       GS trio rapid test$12,000$9000-$15,000Adjusted list prices
      All list prices were adjusted to expected CMS reimbursement rates using a ratio of 0.96. This ratio was derived by comparing mean list prices with 2019 Q4 CMS reimbursement rates for 3 tests for which we had both list prices and reimbursement rates: ES proband, GS proband, and GS trio.
      All children
       SOC (strategy A) testing before Dx$2154
      This cost was derived from the study by Shashi et al,24 which reported a charge of $3285 (2013 USD) for genetic testing performed on patients with suspected genetic conditions—who receive a diagnosis. This average charge included 41% of patients who incurred no charges ($0) for genetic testing because they were diagnosed by clinical criteria only, and 59% of the patients received testing at a charge of $5569 in 2013 USD. We converted this estimate of $5569 from charges to costs (using a cost-to-charge ratio of 0.33) and updated costs from 2013 to 2019 USD using the Consumer Price Index.
      $1077-$3231Shashi et al24
       SOC testing before ES/GS$2154
      This cost was derived from the study by Shashi et al,24 which reported a charge of $3285 (2013 USD) for genetic testing performed on patients with suspected genetic conditions—who receive a diagnosis. This average charge included 41% of patients who incurred no charges ($0) for genetic testing because they were diagnosed by clinical criteria only, and 59% of the patients received testing at a charge of $5569 in 2013 USD. We converted this estimate of $5569 from charges to costs (using a cost-to-charge ratio of 0.33) and updated costs from 2013 to 2019 USD using the Consumer Price Index.
      $1077-$3231Shashi et al24
       Diagnostic Odyssey (SOC testing w/no Dx)$6566
      This cost is derived from the study by Dragojlovic et al,25 which estimated 10-year cost of the diagnostic odyssey for children with suspected genetic conditions. We included the cost estimates for diagnostic tests only. Costs were converted from 2016 CAD to 2019 USD. Future costs (years 2-10) were discounted to present value (year 1) costs using a 3% discount rate.
      $3283-$19,698Dragojlovic et al25
       ES trio standard test$8112$6720-$10,560Adjusted list prices
      All list prices were adjusted to expected CMS reimbursement rates using a ratio of 0.96. This ratio was derived by comparing mean list prices with 2019 Q4 CMS reimbursement rates for 3 tests for which we had both list prices and reimbursement rates: ES proband, GS proband, and GS trio.
       GS trio standard test$10,450$7008-$14,304CMS reimbursement rate 2019 Q4
      After ES and GS testing costs, all ages
       With Dx$135
      These estimates are derived using information from the study by Vrijenhoek et al26 that reported that laboratory, diagnostic, and genetic testing costs are 70% to 90% lower after ES than before and vary on the basis of whether the child does or does not receive a diagnosis.
      $135-$1350Vrijenhoe et al26
       Without Dx$239
      These estimates are derived using information from the study by Vrijenhoek et al26 that reported that laboratory, diagnostic, and genetic testing costs are 70% to 90% lower after ES than before and vary on the basis of whether the child does or does not receive a diagnosis.
      $239-$2390Vrijenhoe et al26
      CAD, Canadian dollar; CMS, Centers for Medicare and Medicaid Services; Dx, diagnosis; ES, exome sequencing; GS, genome sequencing; min, minimum; max, maximum; Q4, fourth quarter; USD, US dollar; w/no, with no.
      a Used in 1-way sensitivity analyses.
      b This cost was derived from the study by Shashi et al,24 which reported a charge of $3285 (2013 USD) for genetic testing performed on patients with suspected genetic conditions—who receive a diagnosis. This average charge included 41% of patients who incurred no charges ($0) for genetic testing because they were diagnosed by clinical criteria only, and 59% of the patients received testing at a charge of $5569 in 2013 USD. We converted this estimate of $5569 from charges to costs (using a cost-to-charge ratio of 0.33) and updated costs from 2013 to 2019 USD using the Consumer Price Index.
      c This cost is derived from the study by Dragojlovic et al,25 which estimated 10-year cost of the diagnostic odyssey for children with suspected genetic conditions. We included the cost estimates for diagnostic tests only. Costs were converted from 2016 CAD to 2019 USD. Future costs (years 2-10) were discounted to present value (year 1) costs using a 3% discount rate.
      d All list prices were adjusted to expected CMS reimbursement rates using a ratio of 0.96. This ratio was derived by comparing mean list prices with 2019 Q4 CMS reimbursement rates for 3 tests for which we had both list prices and reimbursement rates: ES proband, GS proband, and GS trio.
      e These estimates are derived using information from the study by Vrijenhoek et al26 that reported that laboratory, diagnostic, and genetic testing costs are 70% to 90% lower after ES than before and vary on the basis of whether the child does or does not receive a diagnosis.
      Table 3Sensitivity analysis results for primary incremental cost per diagnosis analyses
      Sensitivity Analysis
      This table describes how changing base case assumptions in our model influences our model’s projection for our primary analysis (10-year cost per infant or child diagnosed). In the first row, the far left column identifies the assumption to be altered—in this case, the assumed cost of the diagnostic odyssey and the value of this assumption in the base case analysis. The left portion of the table describes the effect of alternative values for this assumption on the incremental cost of diagnoses in infants. Adopting the first alternative assumption (diagnostic odyssey cost of $3282) means that the estimated incremental cost per diagnosis for GS is $22,157 compared with SOC. Adopting the second alternative assumption (diagnostic odyssey cost of $19,698) means that ES is cost-saving compared with SOC, and the incremental cost per diagnosis for GS is $13,896 compared with ES. The right portion of the table reports corresponding results for our projections for all children.
      (Base Case Assumption)
      Infants (Base Case: GS $15,048/Diagnosis vs SOC)All children (Base Case: GS $27,349/Diagnosis vs SOC)
      First Alternative AssumptionSecond Alternative AssumptionFirst Alternative AssumptionSecond Alternative Assumption
      Value #1Incremental Cost Per DiagnosisValue #2Incremental Cost Per DiagnosisValue #1Incremental Cost Per DiagnosisValue #2Incremental Cost Per Diagnosis
      Cost of diagnostic odyssey ($6566)$3283GS: $22,157/Dx vs SOC$19,698ES: cost-saving vs SOC

      GS: $13,896/Dx vs ES
      $3283GS: $42,122/Dx vs SOC$19,698ES: cost-saving vs SOC

      GS: $25,874/Dx vs ES
      Cost of GS (infants: $12,000 children: $10,450)$9000GS: $7548/Dx vs SOC$15,000ES: $15,541/Dx vs SOC

      GS: $38,896/Dx vs ES
      $7008GS: $8227/Dx vs SOC$14,304ES: $28,824/Dx vs SOC

      GS: $62,147/Dx vs ES
      GS diagnostic rate (infants: 0.49 children: 0.37)0.37ES
      GS has same diagnostic rate and higher cost.
      : $15,541/Dx vs SOC
      0.74GS: $9220/Dx vs SOC0.28ES
      GS has same diagnostic rate and higher cost.
      : $28,824/Dx vs SOC
      0.51GS: $15,338 /Dx vs SOC
      SOC diagnostic rate (infants: 0.09 children: 0.19)0.02ES: $11,551/Dx vs SOC

      GS: $13,896/Dx vs ES
      0.23SOC/GS
      GS has same diagnostic rate and higher cost.
      : $23,076/Dx vs SOC
      0.07ES: $9832/Dx vs SOC

      GS: $25,874/Dx vs ES
      0.28GS: $50,112/Dx vs SOC
      Cost of SOC testing ($2154)$1077SOC/GS
      GS has same diagnostic rate and higher cost.
      : $15,252/Dx vs SOC
      $6462GS: $14,079/Dx vs SOC$1077SOC/GS
      GS has same diagnostic rate and higher cost.
      : $23,296/Dx vs SOC
      $6462ES: $19,729/Dx vs SOC

      GS: $25,874/Dx vs ES
      ES diagnostic rate (infants: 0.37 children: 0.28)0.21GS: $15,048/Dx vs SOC0.43ES: $12,780/Dx vs SOC

      GS: $27,896/Dx vs ES
      0.21GS: $27,349/Dx vs SOC0.43ES: $19,923/Dx vs SOC

      GS: $46,656/Dx vs ES
      ES cost (infants: $10,320 children: $8112)$6720GS: $15,048/Dx vs SOC$13,920GS: $15,048/Dx vs SOC$6720ES: $13,357/Dx vs SOC

      GS: $41,340/Dx vs ES
      $10,560GS: $27,349/Dx vs SOC
      Cost after GS or ES with Dx ($135)$1350GS: $16,536/Dx vs SOC
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      $1350GS: $29,358/Dx vs SOC
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      Cost after GS or ES with no Dx ($239)$2390GS: $17,790/Dx vs SOC
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      $2390GS: $34,877/Dx vs SOC
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      Family members tested (trio)ProbandGS: $7022/Dx vs SOC
      See also Supplemental Table 10.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      ProbandES: cost-saving vs SOC

      GS: $3076/Dx vs ES
      See Supplemental Table 11.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      Reanalysis (no reanalysis)YesES: $12,142/Dx vs SOC

      GS: $15,980/Dx vs ES
      See Supplemental Table 12.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      YesES: $14,227/Dx vs SOC

      GS: $30,078/Dx vs ES
      See Supplemental Table 13.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      Strategies included (SOC, ES, GS)SOC, ESES: $15,543/Dx vs SOC
      See Supplemental Table 14.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      SOC, ESES: $28,822/Dx vs SOC
      See Supplemental Table 15.
      Only 1 alterative assumption was tested.
      Only 1 alterative assumption was tested.
      Cost of SOC testing ($2154) and cost of diagnostic odyssey ($6566)
      Values of these 2 parameters were varied simultaneously between low and high bounds.
      $1077,

      $3283
      SOC/GS: $22,721/Dx vs SOC$6462,

      $19,698
      ES: cost-saving vs SOC

      GS: $13,896 vs ES
      $1077,

      $3283
      SOC/GS: $38,070/Dx vs SOC$6462,

      $19,698
      ES: cost-saving vs SOC

      GS: $25,874/Dx vs ES
      Dx, diagnosis; ES, exome sequencing; GS, genome sequencing; SOC, standard of care.
      a This table describes how changing base case assumptions in our model influences our model’s projection for our primary analysis (10-year cost per infant or child diagnosed). In the first row, the far left column identifies the assumption to be altered—in this case, the assumed cost of the diagnostic odyssey and the value of this assumption in the base case analysis. The left portion of the table describes the effect of alternative values for this assumption on the incremental cost of diagnoses in infants. Adopting the first alternative assumption (diagnostic odyssey cost of $3282) means that the estimated incremental cost per diagnosis for GS is $22,157 compared with SOC. Adopting the second alternative assumption (diagnostic odyssey cost of $19,698) means that ES is cost-saving compared with SOC, and the incremental cost per diagnosis for GS is $13,896 compared with ES. The right portion of the table reports corresponding results for our projections for all children.
      b GS has same diagnostic rate and higher cost.
      c Only 1 alterative assumption was tested.
      j Values of these 2 parameters were varied simultaneously between low and high bounds.

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