How Accurate Is Mass Spectrometry in Forensic Toxicology?

Mass spectrometry (MS) is the "[s]tudy of matter through the formation of gas-phase ions that are characterized using mass spectrometers by their mass, charge, structure, and/or physicochemical properties." ANSI-ASB Standard 098 for Mass Spectral Analysis in Forensic Toxicology § 3.11 (2023). MS has become "the preferred technique for the confirmation of drugs, drug metabolites, relevant xenobiotics, and endogenous analytes in forensic toxicology." Id. at Foreword.

But no "criteria for the acceptance of mass spectrometry data have been ... universally applied by practicing forensic toxicologists." Id. Therefore, the American Academy of Forensic Sciences' Academy Standards Board (ASB) promulgated a "consensus based forensic standard[] within a framework accredited by the American National Standards Institute (ANSI)," id., that provides "minimum requirements." Id. § 1.

To a nonexpert reader (like me), the minimum criteria for the accuracy of MS "confirmation" are not apparent. Consider Section 4.2.1 on "Full-Scan Acquisition using a Single-Stage Low-Resolution Mass Analyzer." It begins with the formal requirement that

[T]he following shall be met when using a single-stage low-resolution mass analyzer in full-scan mode.
a) A minimum of a single diagnostic ion shall be monitored.

It is hard to imagine an MS test method that would not meet the single-ion minimum. Perhaps what makes this requirement meaningful is that the one or more ions must be "diagnostic." However, this adjective begs the question of what the minimum requirement for diagnositicity should be. A "diagnostic ion" is a "molecular ion or fragment ion whose presence and relative abundance are characteristic of the targeted analyte." Id. § 3.4. So what makes an ion "characteristic"? Must it always be present (in some relative abundance) when the "targeted analyte" is in the specimen (at or above some limit of detection)? That would make the ion a marker for the analyte with perfect sensitivity: Pr(ion|analyte) = 1. Even so, it would not be characteristic of the analyte unless its presence is highly specific, that is, unless Pr(no-such-ion|something-else) ≅ 1. But the standard contains no minimum values for sensitivity, specificity, or the likelihood ratio Pr(ion|analyte) / Pr(ion|something-else), which quantifies the positive diagnostic value of a binary test. \1/

This is not to say that there are no minimum requirements in the standard. There certainly are. For example, Section 4.2.1 continues:

b) When monitoring more than one diagnostic ion:
1. ratios of diagnostic ions shall agree with those calculated from a concurrently analyzed reference material given the tolerances shown in Table 1; OR
2. the spectrum shall be compared using an appropriate library search and be above a pre-defined match factor as demonstrated through method validation.

But the standard does not explain how the tolerances in Table 1 were determined. What are the conditional error probabilities that they produce?

Likewise, establishing a critical value for the "match factor" \2/ before using it is essential to a frequentist decision rule, but what are the operating characteristics of the rule? "Method validation" is governed (to the extent that voluntary standards govern anything) by ANSI-ASB 036, Standard Practices for Method Validation in Forensic Toxicology (2019). This standard requires testing to establish that a method is "fit for purpose," but it gives no accuracy rates that would fulfill this vague directive.

Firms that sell antibody test kits for detecting Covid-19 infections no longer can sell whatever they deem is fit for purpose. In May 2020, the FDA stopped issuing emergency use permits for these diagnostic tests without validation showing that they "are 90% 'sensitive,' or able to detect coronavirus antibodies, and 95% 'specific,' or able to avoid false positive results." \3/ Forensic toxicologists do not seem to have proposed such minimum requirements for MS tests.

NOTES

1. Other toxicology standards refer to ASB 098 as if it indicates what it required to apply the label "diagnostic." ANSI/ASB 113, Standard for Identification Criteria in Forensic Toxicology, § 4.5.2 (2023) ("All precursor and product ions are required to be diagnostic per ASB Standard 098, Standard for Mass Spectral Data Acceptance in Forensic Toxicology (2022).").
2. Section 3.13 defines "match factor" as a "mathematical value [a scalar?] that indicates the degree of similarity between an unknown spectrum and a reference spectrum."
3. See How Do Forensic-science Tests Compare to Emergency COVID-19 Tests?, Forensic Sci., Stat. & L., May 5, 2020 (quoting Thomas M. Burton, FDA Sets Standards for Coronavirus Antibody Tests in Crackdown on Fraud, Wall Street J., Updated May 4, 2020 8:24 pm ET, https://www.wsj.com/articles/fda-sets-standards-for-coronavirus-antibody-tests-in-crackdown-on-fraud-11588605373).