To the Editor:
I read the recent publication on disintegrin and metalloprotease protein – 12 (ADAM 12) and ectopic pregnancy (EP) with great interest (1). Rausch et al. concluded that “ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings.” (1)
I agree that the proteomics analysis in this work might lead to the conclusion that ADAM-12 is useful for diagnosis. However, there is no complete classical assessment of diagnostic property (sensitivity, specificity and accuracy). Many other conditions can also present with alteration of ADAM-12. For example, the trisomy is also mentioned as a cause leading to change of ADAM-12 (2). In addition, the cost and availability of the test should be discussed.
I support the conclusion that further assessment is required and it is very long way to accept the use of ADAM-12 for detection of EP in real clinical practice.
Viroj Wiwanitkit, M.D.
1. Rausch ME, Beer L, Sammel MD, Takacs P, Chung K, Shaunik A, Speicher D, Barnhart KT. A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy. Fertil Steril. 2011 Jan 28. [Epub ahead of print]
2. Tørring N, Ball S, Wright D, Sarkissian G, Guitton M, Darbouret B. First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker. Reprod Biol Endocrinol. 2010 Oct 29;8:129.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.02.027
The Authors Respond:
We are very pleased with the interest in our recent article describing the discovery and validation of Adam-12 as a potential biomarker for ectopic pregnancy (1).
While our understanding and management of women with early pregnancy loss has enjoyed incremental improvements over the past few years, there have not been any dramatic breakthrough in decades. Biomarkers that may accurately distinguish an intrauterine vs. an extra uterine gestation, or may accurately distinguish between a viable and a non-viable pregnancy of unknown location, would revolutionize the diagnosis and potential management of women at risk for an ectopic pregnancy.
Biomarkers are often “discovered” by testing the ability of a putative marker in a desired biological pathway to distinguish or identify disease. Alternately, as we have demonstrated in our recent paper, a biomarker can be discovered with an unbiased proteomic approach. The identification and development of a biomarker has distinct phases. The first phase is that of a preclinical exploration to identify promising markers. The second phase is the establishment of a clinical assay to be used on a larger scale. Phase III is testing the utility of the biomarker often with a longitudinal or retrospective cohort. Phase IV is validation of the biomarker, usually in a prospective screening to identify the extent or characteristics of a disease when detected by tests (2,3).
We feel that Adam-12 has reached phase III. We hope a planned prospective cohort will validate the preliminary finding that Adam-12 can distinguish EP from IUP with a sensitivity of 70% and a specificity of 84% (1). A higher cut point may be valuable because of its increased specificity (97%) (1). Alternatively, the use of Adam 12 may be valuable in specific subgroups, such as low gestational age (less than 7 weeks), where we preliminarily demonstrated 100% sensitivity and 72% specificity. Finally, perhaps the greatest utilization of Adam-12 as a biomarker may be as part of a multiple marker panel that can optimize diagnosis with increased accuracy greater than single marker may alone (4).
With continued evidence based quality research, we look forward to a revolution in the diagnosis of women with symptomatic early gestations, who are at risk for ectopic pregnancy.
Kurt Barnhart, MD, MSCEa
Mary Sammel, Sc.D.b
Mary Rausch, MD, MSCEa
David Speicher, PhDc
aDepartment of Obstetrics and Gynecology
University of Pennsylvania
bDepartment of Biostatistics and Epidemiology
University of Pennsylvania School of Medicine
cCenter for Systems and Computational Biology
1. Rausch ME, Beer L, Sammel M, Takacs P, Chung K, Shaunik A, Speicher D, Barnhart K. ADAM-12 as a novel marker for the diagnosis of ectopic pregnancy. Fertil Steril, 2011, EPub ahead of print.
2. Bonassi S, Neri M, Puntoni R. Validation of biomarkers as early predictors of disease. Mutation Research 2001; 480-481: 349-358.
3. McMichael AJ, Hall AJ. The use of biological markers as predictive early-outcome measures in epidemiological research. In: Application of Biomarkers in Cancer Epidemiology. Toniolo P, Boffetta P, Shuker DEG, Rothman N, Hulka B, Pearce N (Eds), International Agency for Research on Cancer, 1997, pp. 281-289.
4. Rausch ME, Sammel M, Takacs P, Chung K, Shaunik A, Barnhart, K. Multiple marker test for the accurate diagnosis of an ectopic pregnancy. Obstet Gynecol In Press, 2010.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.02.028