Bioanalysis Zone

Robert MacNeill: the biomarker bandwagon’s journey over curious calibration curves

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In this instalment of Robert Macneill’s (Covance) column, ‘The Biomarker Bandwagon’s Journey over Curious Calibration Curves’, Robert explores the potential information to be gleaned from calibration curves and how these insights could possibly fuel innovation in the field of biomarker quantification.

Robert MacNeill received his Bachelor’s degree with Honors in Chemistry from Heriot Watt University then his MSc in Analytical Chemistry from the University of Huddersfield, both in the United Kingdom. Robert is also a Chartered Chemist and a Fellow of the Royal Society of Chemistry. With 22 years of experience in all aspects of quantitative bioanalytical LC–MS/MS method development, 13 of these years heading method development activities within the Princeton site that has housed HLS/Envigo (now Covance), and a regular author and peer reviewer for the journal Bioanalysis, Robert is a recognized expert and innovator in the field.


I don’t think I’ve sensed more of a general buzz about biomarkers than at the moment. They are more pivotally involved in drug development than ever. Like other topics of discussion in the industry, it has seemed to go through ups and downs in terms of discussion intensity over the years, but amidst this and the current state of play it is certainly safe to say that this field is particularly important and engaging, has its fair share of controversy and is not short of analytical challenges.

My R&D team has been fortunate enough to have had a handful of interesting dalliances with addressing these challenges over the years, at least in the LC–MS domain. Then around a year ago, I had the honor of guest editing a special focus issue of Bioanalysis, concerned with the reliability of methods for the quantification of biomarkers using the surrogate matrix approach. That amounted to a very valuable immersion in the goings-on at the time. One aspect it helped to underline was that this surrogate matrix approach (where the ‘matrix’ can often be a simple solution) has proven to be generally the most favored, in the face of the alternative surrogate analyte approach which, although highly potent for reliability, comes with important drawbacks. These drawbacks are the time and expense of synthesizing stable-isotopically labeled analogs, of which two are called for, one as the surrogate analyte itself and the other as the internal standard.

This article is part of Robert MacNeill’s (Covance) quarterly column for Bioanalysis Zone, which focuses on quantitative method design. Click here to read past instalments of the column!

The shared objective in all approaches is proving parallelism, the rugged road to reliability, upon which the ‘Biomarker Bandwagon’ wants to be rolling. For the surrogate matrix/solution approach, demonstrating parallelism can be very challenging. This is where the output, the LC–MS peak area-derived response, translating into the slope of a calibration line which is the defining essence of sensitivity, matches between the surrogate element and the real element within the complete methodology. Such fertile ground for the ‘Biomarker Bandwagon’ to navigate with a view to innovation. Especially for those who enjoy the music being played, a lot of which emanates from the more in-depth utilization and assessment of calibration graphs.

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