CCS Associates’ Howard Higley, Lata Mukundan, and Caroline Sigman are co-authors on an article published in May 2017 in Cytometry Part B: Clinical Cytometry: A QA Program for MRD Testing Demonstrates that Systematic Education can Reduce Discordance among Experienced Interpreters.

Dr. Howard Higley is Director of Scientific Affairs at CCS Associates. He has extensive knowledge of clinical/regulatory/intellectual property requirements for successful medical product registration. Dr. Higley has been the study director/principal investigator on more than 125 pilot and good laboratory practice in vivo research studies designed and performed in industry.

Dr. Lata Mukundan is a Senior Scientist at CCS Associates. She is an immunologist with expertise in multiparametric flow cytometry and its application to minimal residual disease measurement in various hematological malignancies.

Dr. Caroline Sigman is CEO and President of CCS Associates. She has extensive experience in strategic planning for drug biomarker development and management of drug development efforts. Dr. Sigman has specialized knowledge of carcinogenesis, cancer chemoprevention, cancer biomarkers, structure-activity relationships, literature search, critical evaluation of health effects data on chemicals, and research and development strategies for biomedical products.


Minimal residual disease (MRD) in B lymphoblastic leukemia (B-ALL) by flow cytometry (FCM) is an established prognostic factor used to adjust treatment in most pediatric therapeutic protocols. MRD in B-ALL has been standardized by the Children’s Oncology Group (COG) in North America, but not routine clinical labs. The Foundation for National Institutes of Health sought to harmonize MRD measurement among COG, oncology groups, and academic, community, and government laboratories. Listmode data from post-induction marrows were distributed from a reference lab to seven different clinical FCM labs with variable experience in B-ALL MRD. Labs were provided with the COG protocol. Files from 15 cases were distributed to the seven labs. Educational sessions were implemented, and 10 more listmode file cases were analyzed. Among 105 initial challenges, the overall discordance rate was 26%. In the final round, performance improved considerably; out of 70 challenges, there were five false positives and one false negative (9% discordance), and no quantitative discordance. Four of six deviations occurred in a single lab. Three samples with hematogones were still misclassified as MRD. Despite the provision of the COG standardized analysis protocol, even experienced laboratories require an educational component for B-ALL MRD analysis by FCM. Recognition of hematogones remains challenging for some labs when using the COG protocol. The results from this study suggest that dissemination of MRD testing to other North American laboratories as part of routine clinical management of B-ALL is possible but requires additional educational components to complement standardized methodology.

The full paper can be found here.

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