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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 1  |  Page : 7-9

Suggested modification of Janus associated kinase 2-tree algorithm for the detection of Janus associated kinase 2 V617F-positive polycythemia rubra vera patients in Pakistani population


1 Department of Hematology, CMH, Lahore, Pakistan
2 Department of Hematology, Shifa Hospital, Karachi, Pakistan

Date of Submission18-Sep-2019
Date of Acceptance16-Dec-2019
Date of Web Publication13-Mar-2020

Correspondence Address:
Dr. Mohammad Abdul Naeem
Department of Hematology, CMH, Lahore
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_60_19

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  Abstract 

OBJECTIVE: The Janus associated kinase-2 (JAK2 mutation V617F and exon 12) is detected in most polycythemia vera (PV) patients. It can easily be picked up by real-time polymerase chain reaction (PCR). This technique is easy to perform and is very sensitive requiring minimally invasive techniques. The decision when to order JAK2 mutation test by PCR is important to curb its wastage. To save precious laboratory resources, a peripheral blood finding-based algorithm adjusted to hemoglobin levels of patients (PV) in Pakistan has been purposed, which is a modification of algorithm recently developed by Mahe et al. for the rationalization of JAK2 analysis.
METHODS: To assist with the screening of patients being considered for JAK mutation for PV patients in the Pakistani population, we modified clinical decision rule “JAK2-tree” as modified JAK2-tree based on patients' full blood count.
RESULTS: We tested both classical and modified JAK2-tree algorithms on two independent data sets, one an unselected population-based sample comprising 51 individuals and other on historical clinical laboratory referral set comprising 51 JAK2-positive cases of PV. Sensitivity for both the algorithms was calculated and compared.
CONCLUSION: Our work supports a “modified” decision-tree-based screening approach for Pakistani population to optimize the selection of patients most appropriate for JAK2 V617F testing.

Keywords: Janus associated kinase 2-tree, modified, Pakistani population


How to cite this article:
Naeem MA, Iqbal M. Suggested modification of Janus associated kinase 2-tree algorithm for the detection of Janus associated kinase 2 V617F-positive polycythemia rubra vera patients in Pakistani population. J Appl Hematol 2020;11:7-9

How to cite this URL:
Naeem MA, Iqbal M. Suggested modification of Janus associated kinase 2-tree algorithm for the detection of Janus associated kinase 2 V617F-positive polycythemia rubra vera patients in Pakistani population. J Appl Hematol [serial online] 2020 [cited 2020 May 27];11:7-9. Available from: http://www.jahjournal.org/text.asp?2020/11/1/7/280544


  Introduction Top


The criteria published by the World Health Organization (WHO) for the diagnosis of polycythemia vera (PV) have never been evaluated in the Pakistani population so far.[1] The 2016 WHO criteria for the diagnosis of PV include three major criteria and one minor criterion. Major criteria include hemoglobin (Hb) levels of 16.5 g/dl in men and 16 g/dl in women, or other evidence of increased red cell volume or hematocrit (Hct),[2] and presence of JAK2 V617F or JAK2 exon 12 mutation and bone marrow biopsy, showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation.[3] Minor criterion includes serum erythropoietin (EPO) levels below the reference range for normal. The JAK2 gene at chromosome 9p24 encodes a tyrosine kinase involved in cytokine receptor signaling through the STAT pathway. When constitutively activated, most often by way of the JAK2 Val 617 Phe (V617F) mutation, the result is an over-responsive kinase to even low-level cytokine stimulation (including EPO). The JAK2 V617F and JAK2 mutations (exon 12) are present in almost every PV patients.[4],[5] The clinical indication to order JAK2 mutation by polymerase chain reaction has been under debate nowadays. Usually, the decision to proceed with JAK2 testing is based on the demonstration of an increase in Hb or Hct. To assist screening of patients being considered for JAK2 testing, Mahe et al. developed a clinical decision rule, “JAK2-tree,” which can be easily applied to basic full blood count (FBC) parameters, such as Hb, platelet, and white blood cell counts (total leukocyte count [TLC]). However, JAK2-tree may be inadequate for diagnosing “early-stage” PV in our local population as there is a major difference in normal reference ranges for Hb in our and Western population.[6] We retrospectively evaluated the accuracy of both JAK2-tree and modified JAK2-tree in diagnosing PV, especially in “early-stage” patients in the Pakistani population [Figure 1].[6]
Figure 1: Janus associated kinase-2-tree algorithm

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  Methods Top


To assist with the screening of patients being considered for JAK mutation for PV patients in Pakistani population, we modified clinical decision rule “JAK2-tree” as modified JAK2-tree based on patients' FBC. We retrospectively analyzed data of 51 randomly selected JAK2 V617-positive patients with similar number of individuals from normal population. We calculated their mean values for their Hb (g/l) levels, TLC, and platelet count. Based on the data obtained, we purposed a modified JAK2-tree algorithm where cutoff for Hb in males was 16 g/dl instead of 16.5 g/dl, and for females, it was 15.5 g/dl instead of 16 g/dl. We calculated the sensitivity of both classical and modified JAK2 on data sets of both normal and JAK2 population using IBM Statistical Package for the Social Sciences for windows, version 24.0 (IBM Corp., Armonk, N.Y., USA).

Results

We tested classical and modified JAK2-tree on two independent data sets, one historical clinical laboratory referral set of 51 individuals [Table 1] and the other referral set comprising 51 JAK2-positive cases of PV [Table 2]. We found sensitivities for classical and modified JAK2 to be 11.7% and 23.5%, respectively, for historical clinical laboratory referral set against classical JAK2-tree, which was 70.5% and 88.2% positivity for known cases of JAK2. Thus, modified JAK2-tree if applied to our historical laboratory referral dataset would have reduced JAK2 V617F testing volume over the period of evaluation by 25%.
Table 1: CMH Lahore retrospective data set Janus associated kinase 2 confusion matrix of historical clinical laboratory referral set

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Table 2: CMH Lahore retrospective data set Janus associated kinase 2 confusion matrix, Janus associated kinase 2-positive cases

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  Discussion Top


The modified JAK2-tree algorithm could be used as a simple screening tool to select patients most appropriate for JAK2 V617F mutation testing to diagnose PV. This algorithm can easily be applied using the routine FBC parameters. Our study has shown it to have a positive predictive value of 95% and negative predictive value of 96% for the detection of JAK2-positive patients. The JAK2-tree algorithm developed by Mahe et al. demonstrated a sensitivity of 94% and a negative predictive value of 92% for the prediction of a JAK2 V617F mutation in their population, which are similar to our study. It is highly recommended that only modified JAK2-tree may be applied to in our population to rationalize the use of JAK2 testing. Further studies are however required to support our findings. The modified JAK2-tree for PV is not designed to be used in predicting thrombosis at unusual sites or to provide molecular confirmation of a previous clinical diagnosis of an myeloproliferative neoplasm or to influence therapy.[7],[8],[9]


  Conclusion Top


Clinical rules should be applied to expensive laboratory tests to reduce costs and unnecessary wastage.[10],[11] Simple clinical decision rules such as “modified JAK2-tree for PV” can assist in appropriate test ordering and detecting underdiagnosed cases in our population. Further studies are suggested in this regard.

Ethics approval

The study was approved by CMH Lahore Ethical Committee.

Open access

This is an open access article distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build on this work noncommercially, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is noncommercial.

Acknowledgments

We wish to thank the CMH Lahore Data Management Teams, as well as the members of the Molecular Haematology Laboratory, for their contributions to this project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 2007;110:1092-7.  Back to cited text no. 1
    
2.
Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood cancer J 2018;8:1-1.  Back to cited text no. 2
    
3.
Spivak JL, Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: An alternative proposal. Blood 2008;112:231-9.  Back to cited text no. 3
    
4.
Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-negative classical myeloproliferative neoplasms: Critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29:761-70.  Back to cited text no. 4
    
5.
Wang YL, Vandris K, Jones A, Cross NC, Christos P, Adriano F, et al. JAK2 Mutations are present in all cases of polycythemia vera. Leukemia 2008;22:1289.  Back to cited text no. 5
    
6.
Mahe E, Pedersen KM, Çolak Y, Bojesen SE, Lynch T, Sinclair G, et al. JAK2-tree: A simple CBC-based decision rule to guide appropriate JAK2 V617F mutation testing. J Clin Pathol 2019;72:172-6.  Back to cited text no. 6
    
7.
Silver RT, Chow W, Orazi A, Arles SP, Goldsmith SJ. Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis. Blood 2013;122:1881-6.  Back to cited text no. 7
    
8.
Shetty S, Kulkarni B, Pai N, Mukundan P, Kasatkar P, Ghosh K. JAK2 mutations across a spectrum of venous thrombosis cases. Am J Clin Pathol 2010;134:82-5.  Back to cited text no. 8
    
9.
Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: Effects on phenotype, prognosis and change with treatment. Ther Adv Hematol 2011;2:21-32.  Back to cited text no. 9
    
10.
Dalal I, Arpaia E, Dadi H, Kulkarni S, Squire J, Roifman CM. Cloning and characterization of the human homolog of mouse Jak2. Blood 1998;91:844-51.  Back to cited text no. 10
    
11.
Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, et al. Stat5 is essential for the myelo-and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 2000;6:693-704.  Back to cited text no. 11
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

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