Acute myeloid leukemia (AML) is an aggressive disease characterized by the overproduction of immature myeloid cells that accumulate in blood and bone marrow. Integration of genetic findings and clinicopathological information is crucial in establishing the diagnosis, prognosis and determining the therapeutic approach in the management of AML patients. In recent years, the AML classification has evolved from morphology to cytogenetics/molecular genetics-based findings, which is essential in the detection of chromosomal abnormalities and has provided the framework for the diagnosis and risk-stratification in AML. Moreover, with advances in molecular karyotyping such as comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, various limitations of conventional diagnostic approaches have been overcome. Hence, this review focuses on the insights into molecular karyotyping using CGH and SNP arrays which enable the identification of copy number variations (CNVs) at a higher resolution and facilitate the detection of copy neutral loss of heterozygosity (CN-LOH) otherwise undetectable by conventional cytogenetics. Technical hindrances of these methods (e.g. regions of losses, gains, or “undulating waves”) are also discussed in the context of AML.
| Published in | International Journal of Biomedical Science and Engineering (Volume 6, Issue 2) |
| DOI | 10.11648/j.ijbse.20180602.11 |
| Page(s) | 20-31 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2018. Published by Science Publishing Group |
Acute Myeloid Leukemia, Comparative Genomic Hybridization, Copy Number Variants, Genomic Analysis, Microarray
| [1] | De Kouchkovsky I, Abdul-Hay M. “Acute myeloid leukemia: a comprehensive review and 2016 update.” Blood Cancer J [Internet]. 2016 Jul 1;6(7):e441. Available from: http://www.nature.com/doifinder/10.1038/bcj.2016.50 |
| [2] | Azizah AM, Nor Saleha IT, Noor Hashimah A, Asmah ZA, Mastulu W. Malaysian National Cancer Registry Report 2007-2011. 2015. |
| [3] | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin [Internet]. 2015 Jan;65(1):5–29. Available from: http://doi.wiley.com/10.3322/caac.21254 |
| [4] | Mangantig E, Naing NN, Norsa’adah B, Azlan H. Survival and prognostic factors in Malaysian acute myeloid leukemia patients after allogeneic haematopoietic stem cell transplantation. Int J Hematol [Internet]. 2013 Aug 30;98(2):197–205. Available from: http://link.springer.com/10.1007/s12185-013-1373-1 |
| [5] | Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood [Internet]. 2016 Jan 7;127(1):53–61. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2015-08-604520 |
| [6] | Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. Longo DL, editor. N Engl J Med [Internet]. 2015 Sep 17;373(12):1136–52. Available from: http://www.nejm.org/doi/10.1056/NEJMra1406184 |
| [7] | Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood [Internet]. 2010 Jan 21;115(3):453–74. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2009-07-235358 |
| [8] | Lowenberg B, Downing JR, Burnett A. Acute Myeloid Leukemia. N Engl J Med [Internet]. 1999 Sep 30;341(14):1051–62. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM199909303411407 |
| [9] | Peters JM, Ansari MQ. Multiparameter flow cytometry in the diagnosis and management of acute leukemia. Arch Pathol Lab Med [Internet]. 2011 Jan;135(1):44–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21204710 |
| [10] | Jaso JM, Wang SA, Jorgensen JL, Lin P. Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future. Bone Marrow Transplant [Internet]. 2014 Sep 19;49(9):1129–38. Available from: http://www.nature.com/doifinder/10.1038/bmt.2014.99 |
| [11] | Kaleem Z, Crawford E, Pathan MH, Jasper L, Covinsky MA, Johnson LR, et al. Flow cytometric analysis of acute leukemias. Diagnostic utility and critical analysis of data. Arch Pathol Lab Med [Internet]. 2003 Jan;127(1):42–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12521365 |
| [12] | Khoury H, Dalal BI, Nantel SH, Horsman DE, Lavoie JC, Shepherd JD, et al. Correlation between karyotype and quantitative immunophenotype in acute myelogenous leukemia with t (8;21). Mod Pathol [Internet]. 2004 Oct 4;17(10):1211–6. Available from: http://www.nature.com/articles/3800168 |
| [13] | Domingo E, Moreno C, Sanchez-Ibarrola A, Panizo C, Paramo JA, Merino J. Enhanced sensitivity of flow cytometry for routine assessment of minimal residual disease. Haematologica [Internet]. 2010 Apr 1;95(4):691–2. Available from: http://www.haematologica.org/cgi/doi/10.3324/haematol.2009.018911 |
| [14] | Langebrake C, Brinkmann I, Teigler-Schlegel A, Creutzig U, Griesinger F, Puhlmann U, et al. Immunophenotypic differences between diagnosis and relapse in childhood AML: Implications for MRD monitoring. Cytom Part B Clin Cytom [Internet]. 2005 Jan;63B (1):1–9. Available from: http://doi.wiley.com/10.1002/cyto.b.20037 |
| [15] | Bridge JA. Advantages and limitations of cytogenetic, molecular cytogenetic, and molecular diagnostic testing in mesenchymal neoplasms. J Orthop Sci [Internet]. 2008 May;13(3):273–82. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0949265815322624 |
| [16] | Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood [Internet]. 2016 May 19;127(20):2391–405. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2016-03-643544 |
| [17] | Le Scouarnec S, Gribble SM. Characterising chromosome rearrangements: recent technical advances in molecular cytogenetics. Heredity (Edinb) [Internet]. 2012 Jan 16;108(1):75–85. Available from: http://www.nature.com/doifinder/10.1038/hdy.2011.100 |
| [18] | Ylstra B. BAC to the future! or oligonucleotides: a perspective for micro array comparative genomic hybridization (array CGH). Nucleic Acids Res [Internet]. 2006 Jan 30;34(2):445–50. Available from: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkj456 |
| [19] | Emanuel BS, Saitta SC. From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat Rev Genet [Internet]. 2007 Nov;8(11):869–83. Available from: http://www.nature.com/doifinder/10.1038/nrg2136 |
| [20] | Tchinda J, Lee C. Detecting copy number variation in the human genome using comparative genomic hybridization. Biotechniques [Internet]. 2006 Oct;41(4):385, 387, 389 passim. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17068952 |
| [21] | Wang Y, Li W, Xia Y, Wang C, Tang YT, Guo W, et al. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions. Chan KYK, editor. PLoS One [Internet]. 2015 Apr 28;10(4):e0123081. Available from: http://dx.plos.org/10.1371/journal.pone.0123081 |
| [22] | LaFramboise T. Single nucleotide polymorphism arrays: a decade of biological, computational and technological advances. Nucleic Acids Res [Internet]. 2009 Jul 1;37(13):4181–93. Available from: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkp552 |
| [23] | O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. Blood [Internet]. 2010 Apr 8;115(14):2731–9. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2009-10-201848 |
| [24] | Simons A, Sikkema-Raddatz B, de Leeuw N, Konrad NC, Hastings RJ, Schoumans J. Genome-wide arrays in routine diagnostics of hematological malignancies. Hum Mutat [Internet]. 2012 Jun;33(6):941–8. Available from: http://doi.wiley.com/10.1002/humu.22057 |
| [25] | Cheung SW, Shaw CA, Scott DA, Patel A, Sahoo T, Bacino CA, et al. Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet Part A [Internet]. 2007 Aug 1;143A (15):1679–86. Available from: http://doi.wiley.com/10.1002/ajmg.a.31740 |
| [26] | Valli R, Marletta C, Pressato B, Montalbano G, Lo Curto F, Pasquali F, et al. Comparative genomic hybridization on microarray (a-CGH) in constitutional and acquired mosaicism may detect as low as 8% abnormal cells. Mol Cytogenet [Internet]. 2011;4(1):13. Available from: http://molecularcytogenetics.biomedcentral.com/articles/10.1186/1755-8166-4-13 |
| [27] | Hartmann L, Stephenson CF, Verkamp SR, Johnson KR, Burnworth B, Hammock K, et al. Detection of Clonal Evolution in Hematopoietic Malignancies by Combining Comparative Genomic Hybridization and Single Nucleotide Polymorphism Arrays. Clin Chem [Internet]. 2014 Dec 1;60(12):1558–68. Available from: http://www.clinchem.org/cgi/doi/10.1373/clinchem.2014.227785 |
| [28] | South ST, Lee C, Lamb AN, Higgins AW, Kearney HM. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med [Internet]. 2013 Nov 26;15(11):901–9. Available from: http://www.nature.com/doifinder/10.1038/gim.2013.129 |
| [29] | Lomax B, Tang S, Separovic E, Phillips D, Hillard E, Thomson T, et al. Comparative Genomic Hybridization in Combination with Flow Cytometry Improves Results of Cytogenetic Analysis of Spontaneous Abortions. Am J Hum Genet [Internet]. 2000 May;66(5):1516–21. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0002929707629814 |
| [30] | Bothur-Nowacka J, Jezela-Stanek A, Zaniuk K, Goryluk-Kozakiewicz B, Krajewska-Walasek M, Dobrzańska A. Tetraploidy in the era of molecular karyotyping – What we need to remember. Pediatr Pol [Internet]. 2013 Sep;88(5):467–71. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0031393913001248 |
| [31] | Heinrichs S, Look AT. Identification of structural aberrations in cancer by SNP array analysis. Genome Biol [Internet]. 2007;8(7):219. Available from: http://genomebiology.biomedcentral.com/articles/10.1186/gb-2007-8-7-219 |
| [32] | Heinrichs S, Li C, Look AT. SNP array analysis in hematologic malignancies: avoiding false discoveries. Blood [Internet]. 2010 May 27;115(21):4157–61. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2009-11-203182 |
| [33] | Przybytkowski E, Aguilar-Mahecha A, Nabavi S, Tonellato PJ, Basik M. Ultradense Array CGH and Discovery of Micro-Copy Number Alterations and Gene Fusions in the Cancer Genome. In 2013. p. 15–38. Available from: http://link.springer.com/10.1007/978-1-62703-281-0_2 |
| [34] | Rasi S, Bruscaggin A, Rinaldi A, Cresta S, Fangazio M, De Paoli L, et al. Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia. Leuk Res [Internet]. 2011 Oct;35(10):1419–22. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0145212611002578 |
| [35] | Walter MJ, Payton JE, Ries RE, Shannon WD, Deshmukh H, Zhao Y, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci [Internet]. 2009 Aug 4;106(31):12950–5. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0903091106 |
| [36] | Tiu R V., Gondek LP, O’Keefe CL, Elson P, Huh J, Mohamedali A, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood [Internet]. 2011 Apr 28;117(17):4552–60. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2010-07-295857 |
| [37] | Ewalt M, Galili NG, Mumtaz M, Churchill M, Rivera S, Borot F, et al. DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. Blood Cancer J [Internet]. 2011 Mar;1(3):e9. Available from: http://www.nature.com/doifinder/10.1038/bcj.2011.7 |
| [38] | Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood [Internet]. 2017 Jan 26;129(4):424–47. Available from: http://www.bloodjournal.org/lookup/doi/10.1182/blood-2016-08-733196 |
| [39] | Akagi T, Ogawa S, Dugas M, Kawamata N, Yamamoto G, Nannya Y, et al. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica [Internet]. 2009 Feb 1;94(2):213–23. Available from: http://www.haematologica.org/cgi/doi/10.3324/haematol.13024 |
| [40] | Zhang R, Lee J-Y, Wang X, Xu W, Hu X, Lu X, et al. Identification of Novel Genomic Aberrations in AML-M5 in a Level of Array CGH. Castresana JS, editor. PLoS One [Internet]. 2014 Apr 11;9(4):e87637. Available from: http://dx.plos.org/10.1371/journal.pone.0087637 |
| [41] | Koh K-N, Lee JO, Seo EJ, Lee SW, Suh JK, Im HJ, et al. Clinical Significance of Previously Cryptic Copy Number Alterations and Loss of Heterozygosity in Pediatric Acute Myeloid Leukemia and Myelodysplastic Syndrome Determined Using Combined Array Comparative Genomic Hybridization plus Single-Nucleotide Polymo. J Korean Med Sci [Internet]. 2014;29(7):926. Available from: https://synapse.koreamed.org/DOIx.php?id=10.3346/jkms.2014.29.7.926 |
| [42] | van der Veken LT, Buijs A. Array CGH in Human Leukemia: From Somatics to Genetics. Cytogenet Genome Res [Internet]. 2011;135(3–4):260–70. Available from: https://www.karger.com/Article/FullText/330629 |
| [43] | Meng CY, Noor PJ, Ismail A, Ahid MFM, Zakaria Z. Cytogenetic Profile of de novo Acute Myeloid Leukemia Patients in Malaysia. Int J Biomed Sci [Internet]. 2013 Mar;9(1):26–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23675286 |
| [44] | Enjeti AK, Tien SL, Sivaswaren CR. Cytogenetic abnormalities in de novo acute myeloid leukemia in adults: relation to morphology, age, sex and ethnicity – a single center study from Singapore. Hematol J [Internet]. 2004;5(5):419–25. Available from: http://www.nature.com/doifinder/10.1038/sj.thj.6200544 |
| [45] | Grimwade D, Hills RK, Moorman A V., Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood [Internet]. 2010 Jul 22;116(3):354–65. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2009-11-254441 |
| [46] | Bullinger L, Krönke J, Schön C, Radtke I, Urlbauer K, Botzenhardt U, et al. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia [Internet]. 2010 Feb 17;24(2):438–49. Available from: http://www.nature.com/doifinder/10.1038/leu.2009.263 |
| [47] | Kim KI, Kim T, Kim I-W, Ahn K-S, Yoon S-S, Shin WG, et al. Copy Number Variations in Normal Karyotype Acute Myeloid Leukemia and their Association with Treatment Response. Basic Clin Pharmacol Toxicol [Internet]. 2012 Nov;111(5):317–24. Available from: http://doi.wiley.com/10.1111/j.1742-7843.2012.00904.x |
| [48] | Yi JH, Huh J, Kim H-J, Kim S-H, Kim H-J, Kim Y-K, et al. Adverse Prognostic Impact of Abnormal Lesions Detected by Genome-Wide Single Nucleotide Polymorphism Array–Based Karyotyping Analysis in Acute Myeloid Leukemia With Normal Karyotype. J Clin Oncol [Internet]. 2011 Dec 10;29(35):4702–8. Available from: http://ascopubs.org/doi/10.1200/JCO.2011.35.5719 |
| [49] | Rücker FG, Bullinger L, Schwaenen C, Lipka DB, Wessendorf S, Fröhling S, et al. Disclosure of Candidate Genes in Acute Myeloid Leukemia With Complex Karyotypes Using Microarray-Based Molecular Characterization. J Clin Oncol [Internet]. 2006 Aug 20;24(24):3887–94. Available from: http://ascopubs.org/doi/10.1200/JCO.2005.04.5450 |
| [50] | Mehrotra M, Luthra R, Ravandi F, Sargent RL, Barkoh BA, Abraham R, et al. Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization. Leuk Lymphoma [Internet]. 2014 Nov 21;55(11):2538–48. Available from: http://www.tandfonline.com/doi/full/10.3109/10428194.2014.883073 |
| [51] | Ambayya A, Chang KM, Lim SM, Yegappan S. Novel genomic aberrations detected with customised DNA microarray in Acute Myeloid Leukemia (AML) patients with poor survival. In: Proceedings of XXIXth International Symposium on Technological Innovations in Laboratory Hematology. Milano, Italy: International Journal of Laboratory Hematology; 2016. |
| [52] | Ambayya A, Chang KM, Lim SM, Yegappan S. Identification of germline and somatic aberrations in acute myeloid leukemia genome by using customised DNA microarray. In: Proceedings of XXIXth International Symposium on Technological Innovations in Laboratory Hematology. Milano, Italy: International Journal of Laboratory Hematology; 2016. |
| [53] | Kuhn MWM, Radtke I, Bullinger L, Goorha S, Cheng J, Edelmann J, et al. High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood [Internet]. 2012 Mar 8;119(10):e67–75. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2011-09-380444 |
APA Style
Angeli Ambayya, Andrew Octavian Sasmita, Jameela Sathar, Kian Meng Chang, Zainina Seman, et al. (2018). Application of Molecular Karyotyping in Acute Myeloid Leukemia: A Review. International Journal of Biomedical Science and Engineering, 6(2), 20-31. https://doi.org/10.11648/j.ijbse.20180602.11
ACS Style
Angeli Ambayya; Andrew Octavian Sasmita; Jameela Sathar; Kian Meng Chang; Zainina Seman, et al. Application of Molecular Karyotyping in Acute Myeloid Leukemia: A Review. Int. J. Biomed. Sci. Eng. 2018, 6(2), 20-31. doi: 10.11648/j.ijbse.20180602.11
AMA Style
Angeli Ambayya, Andrew Octavian Sasmita, Jameela Sathar, Kian Meng Chang, Zainina Seman, et al. Application of Molecular Karyotyping in Acute Myeloid Leukemia: A Review. Int J Biomed Sci Eng. 2018;6(2):20-31. doi: 10.11648/j.ijbse.20180602.11
Share This Article
Twitter
Linked In
Facebook
Copy
Download@article{10.11648/j.ijbse.20180602.11,
author = {Angeli Ambayya and Andrew Octavian Sasmita and Jameela Sathar and Kian Meng Chang and Zainina Seman and Sabariah Md Noor and Subramanian Yegappan},
title = {Application of Molecular Karyotyping in Acute Myeloid Leukemia: A Review},
journal = {International Journal of Biomedical Science and Engineering},
volume = {6},
number = {2},
pages = {20-31},
doi = {10.11648/j.ijbse.20180602.11},
url = {https://doi.org/10.11648/j.ijbse.20180602.11},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijbse.20180602.11},
abstract = {Acute myeloid leukemia (AML) is an aggressive disease characterized by the overproduction of immature myeloid cells that accumulate in blood and bone marrow. Integration of genetic findings and clinicopathological information is crucial in establishing the diagnosis, prognosis and determining the therapeutic approach in the management of AML patients. In recent years, the AML classification has evolved from morphology to cytogenetics/molecular genetics-based findings, which is essential in the detection of chromosomal abnormalities and has provided the framework for the diagnosis and risk-stratification in AML. Moreover, with advances in molecular karyotyping such as comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, various limitations of conventional diagnostic approaches have been overcome. Hence, this review focuses on the insights into molecular karyotyping using CGH and SNP arrays which enable the identification of copy number variations (CNVs) at a higher resolution and facilitate the detection of copy neutral loss of heterozygosity (CN-LOH) otherwise undetectable by conventional cytogenetics. Technical hindrances of these methods (e.g. regions of losses, gains, or “undulating waves”) are also discussed in the context of AML.},
year = {2018}
}
TY - JOUR T1 - Application of Molecular Karyotyping in Acute Myeloid Leukemia: A Review AU - Angeli Ambayya AU - Andrew Octavian Sasmita AU - Jameela Sathar AU - Kian Meng Chang AU - Zainina Seman AU - Sabariah Md Noor AU - Subramanian Yegappan Y1 - 2018/07/12 PY - 2018 N1 - https://doi.org/10.11648/j.ijbse.20180602.11 DO - 10.11648/j.ijbse.20180602.11 T2 - International Journal of Biomedical Science and Engineering JF - International Journal of Biomedical Science and Engineering JO - International Journal of Biomedical Science and Engineering SP - 20 EP - 31 PB - Science Publishing Group SN - 2376-7235 UR - https://doi.org/10.11648/j.ijbse.20180602.11 AB - Acute myeloid leukemia (AML) is an aggressive disease characterized by the overproduction of immature myeloid cells that accumulate in blood and bone marrow. Integration of genetic findings and clinicopathological information is crucial in establishing the diagnosis, prognosis and determining the therapeutic approach in the management of AML patients. In recent years, the AML classification has evolved from morphology to cytogenetics/molecular genetics-based findings, which is essential in the detection of chromosomal abnormalities and has provided the framework for the diagnosis and risk-stratification in AML. Moreover, with advances in molecular karyotyping such as comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, various limitations of conventional diagnostic approaches have been overcome. Hence, this review focuses on the insights into molecular karyotyping using CGH and SNP arrays which enable the identification of copy number variations (CNVs) at a higher resolution and facilitate the detection of copy neutral loss of heterozygosity (CN-LOH) otherwise undetectable by conventional cytogenetics. Technical hindrances of these methods (e.g. regions of losses, gains, or “undulating waves”) are also discussed in the context of AML. VL - 6 IS - 2 ER -
Email: