10 False-Negative Immunoassay Drug Screens Uncovered with a Direct to Mass Spectrometry Approach in a Pediatric Population

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Abstract Routine urine drug screening (UDS) is most commonly performed using immunoassays. The risk of false-positive results from immunoassay are well documented. Confirmation of positive results is essential. The risk of false-negative results secondary to high cutoff concentrations is less appreciated and has not been rigorously quantified. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is generally employed for confirmation due to its advantages in molecular specificity and analytical sensitivity.. A broad spectrum direct to LC-MS/MS approach to drug screening was implemented in our laboratory because of these significant advantages over a screen-then-confirm approach. Our study aimed to estimate the false-negative rate of immunoassay screening in a pediatric population. To achieve this goal, we first selected 125 pediatric urine specimens over a 5-month period (approximately 4% of total screens), that were weakly positive for substances including amphetamine/methamphetamine, cocaine/benzoylecgonine, THC, opiates, fentanyl, benzodiazepines, and methadone by LC-MS/MS. These specimens were reanalyzed by immunoassay on a Roche Cobas analyzer according to the manufacturer’s instructions (Roche Diagnostics, USA). Second, we collected 115 random negative urine specimens from routine clinical pediatric urine drug testing from five sites using various immunoassay platforms including Viva-ProE (Siemens Germany), Vitros Assay (Ortho Clinical Diagnostics), Atellica (Siemens Germany) and Roche Diagnostics (USA). These specimens were subjected to LC-MS/MS analysis. Among the 125 LC-MS/MS positive samples, 112 samples (90%) contained compounds that were not detected by immunoassay. Substances most commonly missed by immunoassay were methamphetamine and benzoylecgonine. Among the 115 negative urine specimens from routine immunoassay, 38 sample (33%) were positive for at least one substance when re-examined by LC-MS/MS. LC-MS/MS identified substances in 6 samples that were missed by immunoassay (approximately 5%) and identified 32 samples that contained several therapeutic medications not covered by immunoassay (e.g., lorazepam, ketamine, bupropion, methylphenidate, clonidine, quetiapine, venlafaxine, and naloxone). Fentanyl (n = 5) was also frequently undetected due to its absence from the immunoassay menu at specific study centers. Our study indicates that nearly 1 in 20 pediatric urine drug screens can be falsely negative. This finding spanned multiple clinical environments and analytic platforms. As samples with negative screens are typically not subjected to further testing, potentially important drug exposure in these patients would be missed. Missing illicit substances can lead to the discharge of a child into an unsafe environment. A broader target menu may also lead to detection of unsuspected substances. A direct to LC-MS/MS approach largely eliminates risk of false positive findings but as we show here, significantly lessens the risk of false-negative drug screens.

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