A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders †
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Study Protocol
2.3. Statistical Analysis
3. Results
3.1. Participants
3.2. Cutoff Determination and Assay Performance
3.3. Performance When Using CLIR’s Postanalytical Multivariate Pattern Recognition Tools
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Race/Ethnicity | Study Population | California Birth Data * |
---|---|---|
White | 37.8% | 27.6% |
Hispanic/Latina | 41.6% | 48.8% |
African American/ Black | 5.4% | 5.3% |
Asian/Pacific Islander | 11.0% | 13.6% |
American Indian/ Alaska Native | 0.14% | 0.4% |
Multiracial | - | 2.2% |
Other/Unknown | 4.2% | 2.2% |
Enzyme | DMF [μmol/L/h] | Immunocapture [ng/mL] | MS/MS [μmol/L/h] |
---|---|---|---|
GAA | 7.71 (n = 412, 0.412%) | 7.36 (n = 4,478; 5.003%) | 5.55 (n = 900, 1.005%) |
GBA | 5.02 1 (n = 376, 0.420%) | 5.00 1 (n = 45,105; 50.392%) | 3.95 (n = 1521; 1.699%) |
IDUA | 5.72 1 (n = 268, 0.299%) | 5.79 1 (n = 4372; 4.884%) | 2.1 (n = 312, 0.349%) |
GLA 2 | 11.4 3 (n = 2357, 2.633%) | 39.36 3 (n = 9764; 10.909%) | 8.90 3 (n = 3637; 4.063%) |
GLA (males only) 4 | 8.36 (n = 473, 0.528%) | 27.41 (n = 2931; 3.275%) | 5.95 (n = 354; 0.395%) |
Case | Enzyme/ Gene | DMF [µmol/L/h] | Immunocapture [ng/mL] | MS/MS [µmol/L/h] | 2TT 1 [µmol/L/h] | Genotype Interpretation 2 | Variant 1 | Variant 2 |
---|---|---|---|---|---|---|---|---|
FD #1 | GLA | 9.1 * | 21.0 | 6.3 | 2.5 | VUS | c.352C>T (p.R118C) | NA |
FD #2 | GLA | 4.4 | 12.0 | 3.3 | 1.1 | VUS | c.352C>T (p.R118C) | NA |
FD #3 | GLA | 7.5 | 15.0 | 3.6 | 1.8 | VUS | c.352C>T (p.R118C) | NA |
FD #4 | GLA | 5.8 | 0.0 | 0.2 | 0.0 | P | c.1023A>C (p.E341D) | NA |
FD #5 | GLA | 7.0 | 19.0 * | 4.7 | 1.7 | VUS | c.419A>C (p.K140T) | NA |
FD #6 | GLA | 10.6 * | 10.0 * | 5.9 * | 2.0 | VUS | c.352C>T (p.R118C) | NA |
FD #7 | GLA | 5.5 | 3.0 | 0.7 | 0.0 | P | c.644A>G (p.N215S) | NA |
FD #8 | GLA | 5.6 | 21.0 | 4.8 | 2.5 | VUS | c.352C>T (p.R118C) | NA |
FD #9 | GLA | 7.1 | 9.0 | 2.8 | 0.6 | LP | c.197A>G (p.E66G) | NA |
FD #10 | GLA | 3.9 | 7.0 | 1.5 | 0.0 | LP | c.1088G>A (p.R363H) | NA |
FD #11 | GLA | 6.1 | 6.0 | 2.3 | 0.7 | LP | c.197A>G (p.E66G) | NA |
FD #12 | GLA | 4.3 | 8.0 | 0.5 | 0.0 | LP | c.1088G>A (p.R363H) | NA |
FD #13 | GLA | 5.5 | 5.0 | 2.4 * | 0.6 | VUS | c.70T>A (p.W24R), c.1255A>G (p.N419D) | NA |
FD #14 | GLA | 5.1 | 15.0 | 6.7 * | 2.7 | VUS | c.352C>T (p.R118C) | NA |
FD #15 | GLA | 3.8 | 1.0 | 0.8 | 0.0 | LP | c.593T>C (p.I198T) | NA |
FD #16 | GLA | 5.5 | 0.0 | 1.0 | 0.0 | LP | c.593T>C (p.I198T) | NA |
FD #17 | GLA | 7.7 | 15.0 | 4.8 | 1.4 | VUS | c.352C>T (p.R118C) | NA |
FD #18 | GLA | 3.6 | 9.0 | 3.7 | 1.0 | VUS | c.473C>A (p.T158N) | NA |
FD #19 | GLA | 9.8 | 3.0 | 3.0 | 0.5 | P | c.124A>C (p.M42L) | NA |
FD #20 | GLA | 6.7 | 7.0 | 3.9 | 0.9 | VUS | c.313A>G (p.R105G) | NA |
FD #21 | GLA | 6.7 | 9.0 | 4.5 | 1.2 | VUS | c.352C>T (p.R118C) | NA |
FD #22 | GLA | 6.6 | 16.0 | 6.3 * | 1.0 | VUS | c.419A>C (p.K140T) | NA |
FD #23 | GLA | 7.0 | 6.0 | 4.6 | 1.1 | P | c.639+919G>A | NA |
FD #24 | GLA | 10.0 * | 17.0 * | 4.6 * | 1.1 | VUS | c.122C>G (p.T41S) | NA |
FD #25 | GLA | 6.8 * | 22.0 * | 5.9 * | 1.3 | PD | c.427G>A (p.A143T) | NA |
FD #26 | GLA | 11.2 * | 22.0 * | 5.7 * | 1.3 | PD | c.427G>A (p.A143T) | NA |
FD #27 | GLA | 9.8 * | 22.0 * | 4.8 * | 1.6 | PD | c.427G>A (p.A143T) | NA |
FD #28 | GLA | 6.2 * | 27.0 * | 3.4 * | 0.7 | PD | c.427G>A (p.A143T) | NA |
FD #29 | GLA | 7.2 * | 19.0 * | 3.1 * | 0.7 | PD | c.427G>A (p.A143T) | NA |
FD #30 | GLA | 11.4 * | 15.0 * | 3.9 * | 1.1 | PD | c.427G>A (p.A143T) | NA |
FD #31 | GLA | 6.6 * | 19.0 * | 4.7 * | 1.4 | PD | c.427G>A (p.A143T) | NA |
FD #32 | GLA | 5.4 * | 20.0 * | 4.6 * | 1.2 | PD | c.427G>A (p.A143T) | NA |
FD #33 | GLA | 4.2 * | 13.0 * | 2.8 * | 1.4 | PD | c.427G>A (p.A143T) | NA |
FD #34 | GLA | 6.5 * | 15.0 * | 4.1 * | 1.4 | PD | c.427G>A (p.A143T) | NA |
FD #35 | GLA | 4.9 * | 10.0 * | 2.9 * | 0.7 | PD | c.427G>A (p.A143T) | NA |
FD #36 | GLA | 6.4 * | 10.0 * | 4.0 * | 1.8 | PD | c.427G>A (p.A143T) | NA |
FD #37 | GLA | 4.6 * | 13.0 * | 4.0 * | 0.5 | PD | c.427G>A (p.A143T) | NA |
FD #38 | GLA | 3.7 * | 16.0 * | 3.2 * | 0.9 | PD | c.427G>A (p.A143T) | NA |
FD #39 | GLA | 8.8 * | 16.0 * | 5.2 * | 0.9 | PD | c.427G>A (p.A143T) | NA |
FD #40 | GLA | 5.6 * | 7.0 * | 3.1 * | 0.6 | PD | c.427G>A (p.A143T) | NA |
FD #41 | GLA | 6.0 * | 13.0 * | 3.4 * | 0.6 | PD | c.427G>A (p.A143T) | NA |
FD #42 | GLA | 5.5 * | 11.0 * | 3.8 * | 0.6 | PD | c.427G>A (p.A143T) | NA |
FD #43 | GLA | 6.5 * | 14.0 * | 6.3 * | 1.3 | PD | c.427G>A (p.A143T) | NA |
FD #44 | GLA | 6.4 * | 19.0 * | 4.4 * | 1.1 | PD | c.427G>A (p.A143T) | NA |
FD #45 | GLA | 4.1 * | 18.0 * | 2.1 * | 0.3 | PD | c.427G>A (p.A143T) | NA |
FD #46 | GLA | 7.6 * | 14.0 * | 4.8 * | 0.9 | PD | c.427G>A (p.A143T) | NA |
FD het #1 | GLA | 7.4 * | 18.0 | 7.2 * | 2.2 | P/nd | c.870G>GC,p.M290MI | - |
FD het #2 | GLA | 9.5* | 11.0 | 4.2 | 0.7 | P/nd | c.870G>A,p.M290I | - |
FD het #3 | GLA | 7.5 | 9.0 | 5.5 | 1.6 | P/B | c.937G>T,p.D313Y | c.1000-22C>T |
FD het #4 | GLA | 8.0 * | 16.0 * | 6.5 * | 2.0 | PD/nd | c.427G>A (p.A143T) | - |
GD #1 | GBA | 2.4 | 5.0* | 0.8 | 0 | P/P | c.1226A>G (p.N409S) | c.1226A>G (p.N409S) |
GD #2 | GBA | 1.5 | 0 | 0 | 0 | P/P | c.680A>G (p.N227S) | c.680A>G (p.N227S) |
MPS I | IDUA | 2.9 | 0 | 0.2 | 0 | P/P | c.1205G>A (p.W402X) | c.46_57del (p.(Ser16_Ala19del)) |
PD #1 | GAA | 4.3 | 4.0* | 1.6 | 0.8 | P/VUS | c.-32-13T>G | c.1909C>A (p.L637M) |
PD #2 | GAA | 5.3 | 0 | 1.7 | 1.1 | LP/VUS | c.1292_1295dup p.(Gln433Alafs *74) | c.1019A>G (p.Y340C) |
PD #3 | GAA | 3.8 * | 0 | 0.5 | 0 | P/P | c.-32-13T>G | [c.752C>T (p.S251L); c.761C>T (p.S254L)] |
PD #4 | GAA | 4.4 | 0 | 2.5 | 2.6 | VUS/VUS | c.257C>G (p.P86R) | c.1306C>T (p.R436W) |
PD #5 | GAA | 5.4 | 0 | 2.4 | 0 | P/P | c.752C>T (p.S251L) | c.761C>T (p.S254L) |
PD #6 | GAA | 8.8 | 0 | 2.2 | 1.5 | P/P | c.752C>T (p.S251L) | c.761C>T (p.S254L) |
Test Platform | Immunocapture + 2TT 5 | Immunocapture + CLIR Tools | DMF + 2TT 5 | DMF + CLIR Tools | MS/MS + 2TT 5 | MS/MS + CLIR Tools |
---|---|---|---|---|---|---|
TP | 27 | 24 | 22 | 22 | 23 | 21 |
Sensitivity 1 | 100% | 92% | 82% | 82% | 85% | 78% |
FP 2 | 74 | 2 | 74 | 39 | 74 | 31 |
Reduction in need for 2TT | - | 97% | - | 47% | - | 58% |
FPR 3 | 0.085% | 0.002% | 0.085% | 0.045% | 0.085% | 0.036% |
PPV 4 | 27% | 92% | 23% | 36% | 30% | 40% |
FN | 0 | 3 | 5 | 5 | 4 | 6 |
Test Platform | Immunocapture + 2TT | Immunocapture + CLIR Tools | DMF + 2TT | DMF + CLIR Tools | MS/MS + 2TT | MS/MS + CLIR Tools |
---|---|---|---|---|---|---|
TP | 1 | 1 | 2 | 2 | 2 | 2 |
Sensitivity 1 | 50% | 50% | 100% | 100% | 100% | 100% |
FP 2 | 107 | 1 | 107 | 13 | 107 | 47 |
Reduction in need for 2TT | - | 99% | - | 88% | - | 56% |
FPR 3 | 0.123% | 0.001% | 0.123% | 0.015% | 0.123% | 0.056% |
PPV 4 | 0.9% | 4.1% | 1.8% | 13.3% | 1.8% | 50.0% |
FN | 1 | 1 | 0 | 0 | 0 | 0 |
Test Platform | Immunocapture + 2TT | Immunocapture + CLIR Tools | DMF + 2TT | DMF + CLIR Tools | MS/MS + 2TT | MS/MS + CLIR Tools |
---|---|---|---|---|---|---|
TP | 1 | 1 | 1 | 1 | 1 | 1 |
Sensitivity 1 | 100% | 100% | 100% | 100% | 100% | 100% |
FP 2 | 159 | 15 | 159 | 17 | 159 | 5 |
Reduction in need for 2TT | - | 91% | - | 89% | - | 97% |
FPR 3 | 0.183% | 0.017% | 0.183% | 0.020% | 0.183% | 0.006% |
PPV 4 | 0.6% | 6.3% | 0.6% | 5.6% | 0.6% | 16.7% |
FN | 0 | 0 | 0 | 0 | 0 | 0 |
Test Platform | Immunocapture + 2TT | Immunocapture + CLIR Tools | DMF + 2TT | DMF + CLIR Tools | MS/MS + 2TT | MS/MS + CLIR Tools |
---|---|---|---|---|---|---|
TP | 6 | 5 | 5 | 5 | 6 | 6 |
Sensitivity 1 | 100% | 83% | 83% | 83% | 100% | 100% |
FP 2 | 99 | 7 | 99 | 65 | 99 | 5 |
Reduction in need for 2TT | - | 93% | - | 32% | - | 95% |
FPR 3 | 0.109% | 0.008% | 0.109% | 0.075% | 0.109% | 0.006% |
PPV 4 | 5.9% | 41.7% | 4.8% | 7.1% | 5.9% | 45.5% |
FN | 0 | 1 | 1 | 1 | 0 | 0 |
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Sanders, K.A.; Gavrilov, D.K.; Oglesbee, D.; Raymond, K.M.; Tortorelli, S.; Hopwood, J.J.; Lorey, F.; Majumdar, R.; Kroll, C.A.; McDonald, A.M.; et al. A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. Int. J. Neonatal Screen. 2020, 6, 44. https://doi.org/10.3390/ijns6020044
Sanders KA, Gavrilov DK, Oglesbee D, Raymond KM, Tortorelli S, Hopwood JJ, Lorey F, Majumdar R, Kroll CA, McDonald AM, et al. A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. International Journal of Neonatal Screening. 2020; 6(2):44. https://doi.org/10.3390/ijns6020044
Chicago/Turabian StyleSanders, Karen A., Dimitar K. Gavrilov, Devin Oglesbee, Kimiyo M. Raymond, Silvia Tortorelli, John J. Hopwood, Fred Lorey, Ramanath Majumdar, Charles A. Kroll, Amber M. McDonald, and et al. 2020. "A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders" International Journal of Neonatal Screening 6, no. 2: 44. https://doi.org/10.3390/ijns6020044
APA StyleSanders, K. A., Gavrilov, D. K., Oglesbee, D., Raymond, K. M., Tortorelli, S., Hopwood, J. J., Lorey, F., Majumdar, R., Kroll, C. A., McDonald, A. M., Lacey, J. M., Turgeon, C. T., Tucker, J. N., Tang, H., Currier, R., Isaya, G., Rinaldo, P., & Matern, D. (2020). A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. International Journal of Neonatal Screening, 6(2), 44. https://doi.org/10.3390/ijns6020044