DETECTION OF ? THALASSEMIA CARRIERS BY RED CELL PARAMETERS OBTAINED FROM AUTOMATIC COUNTERS USING MATHEMATICAL FORMULAS
Main Article Content
Keywords
Thalassemia, Prevention, Screening, Mathematical formulas
Abstract
BACKGROUND and Objective: ? thalassemia major is a severe disease with high morbidity. The world prevalence of carriers is around 1.5–7%. The aim of the present study was to find a reliable formula for detecting ? thalassemia carriers using a large database of more than 22,000 samples obtained from a homogeneous population of childbearing age women with 14% of ? thalassemia carriers and to check previously published formulas.
METHODS: We applied a mathematical method based on the support vector machine (SVM) algorithm in the search for a reliable formula that can differentiate between thalassemia carriers and non-carriers, including normal counts or counts suspected to belong to iron-deficient women.
RESULTS: Shine's formula and ours showed >98% sensitivity and >99.77% NPV. All other published formulas gave inferior results.
CONCLUSIONS: We found a reliable formula that can be incorporated into any automatic blood counter to alert health providers to the possibility of a woman being a ? thalassemia carrier. A further simple hemoglobin characterization by HPLC analysis should be performed to confirm the diagnosis, and subsequent family studies should be carried out. Our SVM formula is currently limited to women of fertility age until further analysis in other groups can be performed.
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References
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2. Filon D, Oron V, Krichevski S, Shaag A, Shaag Y, Warren TC, et al. Diversity of beta-globin mutations in Israeli ethnic groups reflects recent historic events. Am J Hum Genet. 1994;54(5):836-43.
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6. Srivastava PC. Differentiation of thalassaemia minor from iron deficiency. Lancet. 1973;2(7821):154-5.
7. England JM, Fraser PM. Differentiation of iron deficiency from thalassaemia trait by routine blood-count. Lancet. 1973;1(7801):449-52.
8. Mentzer WC, Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet. 1973;1(7808):882.
9. Shine I, Lal S. A strategy to detect beta-thalassaemia minor. Lancet. 1977;1(8013):692-4.
10. England JM, Fraser P. Discrimination between iron-deficiency and heterozygous-thalassaemia syndromes in differential diagnosis of microcytosis. Lancet. 1979;1(8108):145-8.
11. Ricerca BM, Storti S, d'Onofrio G, Mancini S, Vittori M, Campisi S, et al. Differentiation of iron deficiency from thalassaemia trait: a new approach. Haematologica. 1987;72(5):409-13.
12. Green R, King R. A new red cell discriminant incorporating volume dispersion for differentiating iron deficiency anemia from thalassemia minor. Blood Cells. 1989;15(3):481-91; discussion 92-5.
13. d'Onofrio G ZG, Ricerca BM , Mancini S , Mango G. Automated measurement of red blood cell microcytosis and hypochromia in iron deficiency and beta-thalassemia trait. Archives of Pathology & Laboratory Medicine. 1992;116(1):84-9.
14. Sonati Mde F, Grotto HZ, Kimura EM, Costa FF. [Differentiation between heterozygotic beta-thalassemia and iron deficiency anemia]. Rev Assoc Med Bras. 1993;39(4):221-3.
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16. Sirdah M, Tarazi I, Al Najjar E, Al Haddad R. Evaluation of the diagnostic reliability of different RBC indices and formulas in the differentiation of the beta-thalassaemia minor from iron deficiency in Palestinian population. Int J Lab Hematol. 2008;30(4):324-30.
17. Ehsani MA, Shahgholi E, Rahiminejad MS, Seighali F, Rashidi A. A new index for discrimination between iron deficiency anemia and beta-thalassemia minor: results in 284 patients. Pak J Biol Sci. 2009;12(5):473-5.
18. Sirachainan N, Iamsirirak P, Charoenkwan P, Kadegasem P, Wongwerawattanakoon P, Sasanakul W, et al. New mathematical formula for differentiating thalassemia trait and iron deficiency anemia in thalassemia prevalent area: a study in healthy school-age children. Southeast Asian J Trop Med Public Health. 2014;45(1):174-82.
19. Miri-Moghaddam E, Sargolzaie N. Cut off Determination of Discrimination Indices in Differential Diagnosis between Iron Deficiency Anemia and beta- Thalassemia Minor. Int J Hematol Oncol Stem Cell Res. 2014;8(2):27-32.
20. Sahli CA, Bibi A, Ouali F, Fredj SH, Dakhlaoui B, Othmani R, et al. Red cell indices: differentiation between beta-thalassemia trait and iron deficiency anemia and application to sickle-cell disease and sickle-cell thalassemia. Clin Chem Lab Med. 2013;51(11):2115-24.
21. Vehapoglu A, Ozgurhan G, Demir AD, Uzuner S, Nursoy MA, Turkmen S, et al. Hematological indices for differential diagnosis of Beta thalassemia trait and iron deficiency anemia. Anemia. 2014;2014:576738.
22. Beyan C, Kaptan K, Ifran A. Predictive value of discrimination indices in differential diagnosis of iron deficiency anemia and beta-thalassemia trait. Eur J Haematol. 2007;78(6):524-6.
23. Ntaios G, Chatzinikolaou A, Saouli Z, Girtovitis F, Tsapanidou M, Kaiafa G, et al. Discrimination indices as screening tests for beta-thalassemic trait. Ann Hematol. 2007;86(7):487-91.
24. Rathod DA, Kaur A, Patel V, Patel K, Kabrawala R, Patel V, et al. Usefulness of cell counter-based parameters and formulas in detection of beta-thalassemia trait in areas of high prevalence. Am J Clin Pathol. 2007;128(4):585-9.
25. Amendolia SR, Cossu, G., Ganadu, M.L., Golosio, B., Masala, G.L., Mura, G.M. A comparative study of K-Nearest Neighbour, Support Vector Machine and Multi-Layer Perceptron for Thalassemia screening. . Chemometrics and Intelligent Lasboratory Systems. 2003;69:13-20.
26. Kiss TL, Ali MA, Levine M, Lafferty JD. An algorithm to aid in the investigation of thalassemia trait in multicultural populations. Arch Pathol Lab Med. 2000;124(9):1320-3.
27. Lafferty JD, Crowther MA, Ali MA, Levine M. The evaluation of various mathematical RBC indices and their efficacy in discriminating between thalassemic and non-thalassemic microcytosis. Am J Clin Pathol. 1996;106(2):201-5.
28. Sargolzaie N, Miri-Moghaddam E. A local equation for differential diagnosis of beta-thalassemia trait and iron deficiency anemia by logistic regression analysis in Southeast Iran. Hemoglobin. 2014;38(5):355-8.
29. Urrechaga E, Aguirre U, Izquierdo S. Multivariable discriminant analysis for the differential diagnosis of microcytic anemia. Anemia. 2013;2013:457834.
30. Zaghloul A, Al-Bukhari TA, Bajuaifer N, Shalaby M, Al-Pakistani HA, Halawani SH, et al. Introduction of new formulas and evaluation of the previous red blood cell indices and formulas in the differentiation between beta thalassemia trait and iron deficiency anemia in the Makkah region. Hematology. 2016;21(6):351-8.
31. Bordbar E, Taghipour M, Zucconi BE. Reliability of Different RBC Indices and Formulas in Discriminating between beta-Thalassemia Minor and other Microcytic Hypochromic Cases. Mediterr J Hematol Infect Dis. 2015;7(1):e2015022.
32. Hisham A.Getta1 HAY, Hameed M. Said Hi & Ha, are new indices in differentiation between Iron deficiency anemia and beta-Thalassaemia trait /A Study in Sulaimani City-Kurdistan/Iraq Journal of Dental and Medical Sciences 2015;14(7):67-72.
33. Hoffmann JJ, Urrechaga E, Aguirre U. Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis. Clin Chem Lab Med. 2015;53(12):1883-94.
34. Schoorl M, Schoorl M, van Pelt J, Bartels PC. Application of Innovative Hemocytometric Parameters and Algorithms for Improvement of Microcytic Anemia Discrimination. Hematol Rep. 2015;7(2):5843.
35. BURGES CJC. A Tutorial on Support Vector Machines for Pattern Recognition. Data Mining and Knowledge
Discovery 1998;2:121-67.
36. Angastiniotis M, Eleftheriou A, Galanello R, Harteveld CL, Petrou M, Traeger-Synodinos J, et al. In: Old J, ed. Prevention of Thalassaemias and Other Haemoglobin Disorders: Volume 1: Principles. 2nd ed. Nicosia, Cyprus; 2013.
37. Rund D, Filon D, Strauss N, Rachmilewitz E, Oppenheim A. Mean corpuscular volume of heterozygotes for beta-thalassemia correlates with the severity of mutations. Blood. 1992;79(1):238-43.
38. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001;79(8):704-12.
39. Wasi P, Disthasongchan P, Na-Nakorn S. The effect of iron deficiency on the levels of hemoglobins A2 and E. J Lab Clin Med. 1968;71(1):85-91.
40. Zaghloul A, Al-Bukhari TA, Bajuaifer N, Shalaby M, Al-Pakistani HA, Halawani SH, et al. Introduction of new formulas and evaluation of the previous red blood cell indices and formulas in the differentiation between beta thalassemia trait and iron deficiency anemia in the Makkah region. Hematology. 2016.
41. Rahim F, Keikhaei B. Better differential diagnosis of iron deficiencyanemia from beta-thalassemia trait. Turk J Haematol. 2009;26(3):138-45.
42. Romero Artaza J, Carbia CD, Ceballo MF, Diaz NB. [Red cell distribution width (RDW): its use in the characterization of microcytic and hypochromic anemias]. Medicina (B Aires). 1999;59(1):17-22.
43. Ismail M, Patel Nisar G. Evaluation of the Diagnostic Accuracy of Twelve Discrimination Indices for Differentiating ?-thalassemia Trait from Iron Deficiency Anemia. Indian Journal of Public Health Research & Development. 2016;7(1):104.
2. Filon D, Oron V, Krichevski S, Shaag A, Shaag Y, Warren TC, et al. Diversity of beta-globin mutations in Israeli ethnic groups reflects recent historic events. Am J Hum Genet. 1994;54(5):836-43.
3. Koren A, Profeta L, Zalman L, Palmor H, Levin C, Zamir RB, et al. Prevention of beta Thalassemia in Northern Israel - a Cost-Benefit Analysis. Mediterr J Hematol Infect Dis. 2014;6(1):e2014012.
4. Koren A, Zalman L, Palmor H, Ekstein E, Schneour Y, Schneour A, et al. [The prevention programs for beta thalassemia in the Jezreel and Eiron valleys: results of fifteen years experience]. Harefuah. 2002;141(11):938-43, 1210.
5. Cazzavillan M, Barbui T, Franchi F, Chisesi T, Dini E. Comparison of Price-Jones curves obtained with an electronic corpuscle counter in normal subjects and in patients with thalassaemia and iron deficiency. Haematologia (Budap). 1973;7(3):333-7.
6. Srivastava PC. Differentiation of thalassaemia minor from iron deficiency. Lancet. 1973;2(7821):154-5.
7. England JM, Fraser PM. Differentiation of iron deficiency from thalassaemia trait by routine blood-count. Lancet. 1973;1(7801):449-52.
8. Mentzer WC, Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet. 1973;1(7808):882.
9. Shine I, Lal S. A strategy to detect beta-thalassaemia minor. Lancet. 1977;1(8013):692-4.
10. England JM, Fraser P. Discrimination between iron-deficiency and heterozygous-thalassaemia syndromes in differential diagnosis of microcytosis. Lancet. 1979;1(8108):145-8.
11. Ricerca BM, Storti S, d'Onofrio G, Mancini S, Vittori M, Campisi S, et al. Differentiation of iron deficiency from thalassaemia trait: a new approach. Haematologica. 1987;72(5):409-13.
12. Green R, King R. A new red cell discriminant incorporating volume dispersion for differentiating iron deficiency anemia from thalassemia minor. Blood Cells. 1989;15(3):481-91; discussion 92-5.
13. d'Onofrio G ZG, Ricerca BM , Mancini S , Mango G. Automated measurement of red blood cell microcytosis and hypochromia in iron deficiency and beta-thalassemia trait. Archives of Pathology & Laboratory Medicine. 1992;116(1):84-9.
14. Sonati Mde F, Grotto HZ, Kimura EM, Costa FF. [Differentiation between heterozygotic beta-thalassemia and iron deficiency anemia]. Rev Assoc Med Bras. 1993;39(4):221-3.
15. Lima CS, Reis AR, Grotto HZ, Saad ST, Costa FF. Comparison of red cell distribution width and a red cell discriminant function incorporating volume dispersion for distinguishing iron deficiency from beta thalassemia trait in patients with microcytosis. Sao Paulo Med J. 1996;114(5):1265-9.
16. Sirdah M, Tarazi I, Al Najjar E, Al Haddad R. Evaluation of the diagnostic reliability of different RBC indices and formulas in the differentiation of the beta-thalassaemia minor from iron deficiency in Palestinian population. Int J Lab Hematol. 2008;30(4):324-30.
17. Ehsani MA, Shahgholi E, Rahiminejad MS, Seighali F, Rashidi A. A new index for discrimination between iron deficiency anemia and beta-thalassemia minor: results in 284 patients. Pak J Biol Sci. 2009;12(5):473-5.
18. Sirachainan N, Iamsirirak P, Charoenkwan P, Kadegasem P, Wongwerawattanakoon P, Sasanakul W, et al. New mathematical formula for differentiating thalassemia trait and iron deficiency anemia in thalassemia prevalent area: a study in healthy school-age children. Southeast Asian J Trop Med Public Health. 2014;45(1):174-82.
19. Miri-Moghaddam E, Sargolzaie N. Cut off Determination of Discrimination Indices in Differential Diagnosis between Iron Deficiency Anemia and beta- Thalassemia Minor. Int J Hematol Oncol Stem Cell Res. 2014;8(2):27-32.
20. Sahli CA, Bibi A, Ouali F, Fredj SH, Dakhlaoui B, Othmani R, et al. Red cell indices: differentiation between beta-thalassemia trait and iron deficiency anemia and application to sickle-cell disease and sickle-cell thalassemia. Clin Chem Lab Med. 2013;51(11):2115-24.
21. Vehapoglu A, Ozgurhan G, Demir AD, Uzuner S, Nursoy MA, Turkmen S, et al. Hematological indices for differential diagnosis of Beta thalassemia trait and iron deficiency anemia. Anemia. 2014;2014:576738.
22. Beyan C, Kaptan K, Ifran A. Predictive value of discrimination indices in differential diagnosis of iron deficiency anemia and beta-thalassemia trait. Eur J Haematol. 2007;78(6):524-6.
23. Ntaios G, Chatzinikolaou A, Saouli Z, Girtovitis F, Tsapanidou M, Kaiafa G, et al. Discrimination indices as screening tests for beta-thalassemic trait. Ann Hematol. 2007;86(7):487-91.
24. Rathod DA, Kaur A, Patel V, Patel K, Kabrawala R, Patel V, et al. Usefulness of cell counter-based parameters and formulas in detection of beta-thalassemia trait in areas of high prevalence. Am J Clin Pathol. 2007;128(4):585-9.
25. Amendolia SR, Cossu, G., Ganadu, M.L., Golosio, B., Masala, G.L., Mura, G.M. A comparative study of K-Nearest Neighbour, Support Vector Machine and Multi-Layer Perceptron for Thalassemia screening. . Chemometrics and Intelligent Lasboratory Systems. 2003;69:13-20.
26. Kiss TL, Ali MA, Levine M, Lafferty JD. An algorithm to aid in the investigation of thalassemia trait in multicultural populations. Arch Pathol Lab Med. 2000;124(9):1320-3.
27. Lafferty JD, Crowther MA, Ali MA, Levine M. The evaluation of various mathematical RBC indices and their efficacy in discriminating between thalassemic and non-thalassemic microcytosis. Am J Clin Pathol. 1996;106(2):201-5.
28. Sargolzaie N, Miri-Moghaddam E. A local equation for differential diagnosis of beta-thalassemia trait and iron deficiency anemia by logistic regression analysis in Southeast Iran. Hemoglobin. 2014;38(5):355-8.
29. Urrechaga E, Aguirre U, Izquierdo S. Multivariable discriminant analysis for the differential diagnosis of microcytic anemia. Anemia. 2013;2013:457834.
30. Zaghloul A, Al-Bukhari TA, Bajuaifer N, Shalaby M, Al-Pakistani HA, Halawani SH, et al. Introduction of new formulas and evaluation of the previous red blood cell indices and formulas in the differentiation between beta thalassemia trait and iron deficiency anemia in the Makkah region. Hematology. 2016;21(6):351-8.
31. Bordbar E, Taghipour M, Zucconi BE. Reliability of Different RBC Indices and Formulas in Discriminating between beta-Thalassemia Minor and other Microcytic Hypochromic Cases. Mediterr J Hematol Infect Dis. 2015;7(1):e2015022.
32. Hisham A.Getta1 HAY, Hameed M. Said Hi & Ha, are new indices in differentiation between Iron deficiency anemia and beta-Thalassaemia trait /A Study in Sulaimani City-Kurdistan/Iraq Journal of Dental and Medical Sciences 2015;14(7):67-72.
33. Hoffmann JJ, Urrechaga E, Aguirre U. Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis. Clin Chem Lab Med. 2015;53(12):1883-94.
34. Schoorl M, Schoorl M, van Pelt J, Bartels PC. Application of Innovative Hemocytometric Parameters and Algorithms for Improvement of Microcytic Anemia Discrimination. Hematol Rep. 2015;7(2):5843.
35. BURGES CJC. A Tutorial on Support Vector Machines for Pattern Recognition. Data Mining and Knowledge
Discovery 1998;2:121-67.
36. Angastiniotis M, Eleftheriou A, Galanello R, Harteveld CL, Petrou M, Traeger-Synodinos J, et al. In: Old J, ed. Prevention of Thalassaemias and Other Haemoglobin Disorders: Volume 1: Principles. 2nd ed. Nicosia, Cyprus; 2013.
37. Rund D, Filon D, Strauss N, Rachmilewitz E, Oppenheim A. Mean corpuscular volume of heterozygotes for beta-thalassemia correlates with the severity of mutations. Blood. 1992;79(1):238-43.
38. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001;79(8):704-12.
39. Wasi P, Disthasongchan P, Na-Nakorn S. The effect of iron deficiency on the levels of hemoglobins A2 and E. J Lab Clin Med. 1968;71(1):85-91.
40. Zaghloul A, Al-Bukhari TA, Bajuaifer N, Shalaby M, Al-Pakistani HA, Halawani SH, et al. Introduction of new formulas and evaluation of the previous red blood cell indices and formulas in the differentiation between beta thalassemia trait and iron deficiency anemia in the Makkah region. Hematology. 2016.
41. Rahim F, Keikhaei B. Better differential diagnosis of iron deficiencyanemia from beta-thalassemia trait. Turk J Haematol. 2009;26(3):138-45.
42. Romero Artaza J, Carbia CD, Ceballo MF, Diaz NB. [Red cell distribution width (RDW): its use in the characterization of microcytic and hypochromic anemias]. Medicina (B Aires). 1999;59(1):17-22.
43. Ismail M, Patel Nisar G. Evaluation of the Diagnostic Accuracy of Twelve Discrimination Indices for Differentiating ?-thalassemia Trait from Iron Deficiency Anemia. Indian Journal of Public Health Research & Development. 2016;7(1):104.