Danyel Hermes Tacker

On May 6, 2024, the United States Food and Drug Administration (FDA) published the final rule for oversight of laboratory-developed tests (LDTs) ( 1). The FDA claims (a) the final rule is necessary to ensure the accuracy and reliability of LDTs and (b) the agency was given authority by the government to regulate LDTs in the same manner as medical device manufacturers. Although the final rule is published, there remains on-going debate for both of these claims in the medical community ( 2–4). Further, the FDA has yet to provide adequate information on how their infrastructure will support the timely review of LDTs ( 1). There are notable infrastructure issues within the FDA’s established programs that may foreshadow future LDT regulation activity. Particularly, in 2022 the Reagan-Udall Foundation emphasized the agency’s shortcomings in their current structure, including over 2000 vacancies across the FDA, as well as poor communication and leadership gaps ( 5). Similarly, the U.S. Government Accountability Office reported that the FDA has postponed approximately 8000 foreign and domestic drug manufacturing facility inspections, which mirrors the delays seen for molecular and antibody testing reviews during the pandemic ( 6, 7). Contrary to these noteworthy issues and to circumvent the volume of anticipated LDT submissions, the FDA has (a) categorized LDTs to focus immediate regulation on fewer LDT types; (b) included a partial “grandfather” clause, whereby LDT in use prior to May 6, 2024, may fall under general enforcement discretion and would require registration and implementation of various controls and reporting structures; and (c) proposed to scale up third-party review organization (3PRO) activity ( 1).

Background: The conventional single-analyte delta check, utilized for identifying intravenous fluid contamination and other preanalytical errors, is known to flag many specimens reflecting true patient status changes. This study aimed to derive delta check rules that more accurately identify contamination. Methods: Results for calcium, creatinine, glucose, sodium, and potassium were retrieved from 326 103 basic or comprehensive metabolic panels tested between February 2021 and January 2022. In total, 7934 specimens showed substantial result changes, of which 1489 were labeled as either contaminated or non-contaminated based on chart review. These labeled specimens were used to derive logistic regression models and to select the most predictive single-analyte delta checks for 4 common contaminants. Their collective performance was evaluated using a test data set from October 2023 comprising 14 717 specimens. Results: The most predictive single-analyte delta checks included a calcium change by ≤−24% for both saline and Plasma-Lyte A contamination, a potassium increase by ≥3.0 mmol/L for potassium contamination, and a glucose increase by ≥400 mg/dL (22.2 mmol/L) for dextrose contamination. In the training data sets, multi-analyte logistic regression models performed better than single-analyte delta checks. In the test data set, logistic regression models and single-analyte delta checks demonstrated collective alert rates of 0.58% (95% CI, 0.46%–0.71%) and 0.60% (95% CI, 0.49%–0.74%), respectively, along with collective positive predictive values of 79% (95% CI, 70%–89%) and 77% (95% CI, 68%–87%). Conclusions: Single-analyte delta checks selected by logistic regression demonstrated a low false alert rate.

In evaluation of systemic lupus erythematosus (SLE), anti–double-stranded DNA antibodies (anti-dsDNA) play a significant role in diagnosis, monitoring SLE activity, and assessing prognosis. However, evaluations of the performance and limitations for recently developed methods for anti-dsDNA assessment are sparse. Specimens used for antinuclear antibody testing (n = 129) were evaluated for anti-dsDNA assay comparability across 4 medical centers in the United States. The methods compared were Werfen Quanta Lite dsDNA, Zeus Scientific dsDNA Enzyme Immunoassay, Bio-Rad multiplex immunoassay (MIA) dsDNA, ImmunoConcepts Crithidia, and Bio-Rad Laboratories Crithidia. For quantitative anti-dsDNA measurements, Spearman’s correlation coefficient was highest between Zeus and Werfen (ρ = 0.86; CI, 0.81-0.90; P < .0001). Comparison of MIA to Werfen or Zeus yielded similar results to each other (ρ = 0.58; CI, 0.44-0.68; P < .0001; and ρ = 0.59; CI, 0.46-0.69; P < .0001, respectively), but lower than the correlation between Zeus and Werfen. Positive concordance between assays ranged from 31.4% to 97.1%, and negative concordance between assays ranged from 58.5% to 100%. The detection of anti-dsDNA in those with SLE diagnosis ranged from 50.9% to 77.4% for quantitative assays and 15.1% to 24.5% for Crithidia assays. Current quantitative anti-dsDNA assays are not interchangeable for patient follow-up. Crithidia-based assays demonstrate high negative concordance and lack positive concordance among the methods.

This study retrospectively compared false-positive result frequencies of 3 syphilis serology screening tests and assessed whether false positivity was associated with pregnancy and age. Results for 3 screening tests were retrieved from the laboratory database, including rapid plasma reagin (RPR) assay between October 2016 and September 2019, BioPlex 2200 Syphilis Total immunoassay between May 2020 and January 2022, and Alinity i Syphilis TP assay between February 2022 and April 2023. The false-positive result frequencies were calculated based on testing algorithm criteria. False-positive result frequency for BioPlex was 0.61% (90/14,707), significantly higher than 0.29% (50/17,447) for RPR and 0.38% (55/14,631) for Alinity (both P < .01). Patients with false-positive results were significantly older than patients with nonreactive results for RPR (median age: 36 vs 28, P < .001), but not for BioPlex or Alinity. For all 3 tests, the positive predictive values in pregnant women were lower than those in nonpregnant women or men. However, pregnant women did not exhibit a higher false-positive result frequency. Although false-positive result frequencies were low overall for all 3 syphilis serology tests, there is a significant difference between different tests. Pregnancy was not associated with more false-positive results for all 3 tests.

Background: Deaths attributable to fentanyl (FEN, a synthetic opioid) are high in Appalachia and highest in West Virginia. The goal of the study was to determine FEN prevalence among specimens submitted for definitive opioid testing and monitor responses to provider notifications of unexpected FEN findings during Q1 2020. Methods: All definitive opioid test data were reviewed daily for FEN signatures in Q1 2020. Unexpected FEN results were communicated to providers and monitored for 10 days to record actions taken. Prevalence data were categorized. Behavioral Medicine (BMED) leaders analyzed January data and implemented FEN screening in the clinic. BMED Q1 clinic visits and order volumes for drug screens were reviewed after Q1. Results: FEN positivity was 11% in Q1; >60% of findings were unexpected. Actions were taken for 54% of notifications in January but only 18% in March. Notifications required 70 hours of combined laboratory effort each month. BMED providers ordered 44% of definitive opioid tests and 69% of definitive FEN tests. Data prompted the addition of FEN to routine drug screen panels in the laboratory, and a 10% random FEN screening rate in the BMED opioid use disorder clinics (COAT). Conclusions: Prevalence of FEN positivity was higher than initially expected, even for this region in Appalachia. Expanded presence of FEN screening should assist BMED providers with clinical efforts and help identify patients in need of intervention/therapy.

Background. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated significant effects on low-density lipoprotein (LDL) cholesterol and nonhigh density lipoprotein (HDL) cholesterol. To date, there have been limited reports on the effect of PCSK9 inhibitors on remnant cholesterol. Objectives. Assess the effect of PCSK9 inhibitors on nonfasting remnant cholesterol in a real world population. Identify whether pretreatment triglyceride levels are associated with PCSK9 inhibition success as indicated by changes in remnant cholesterol levels. Methods. Patients in our adult lipid clinic (n = 109) receiving PCSK9 inhibition for atherosclerotic cardiovascular disease or familial hypercholesterolemia who had available pre- and post-PCSK9 inhibition standard nonfasting lipid data were, retrospectively, selected for data analysis. Remnant cholesterol was the difference between non-HDL and LDL cholesterol. LDL cholesterol was measured directly and calculated from Friedewald and Martin/Hopkins methods. Data were analyzed using repeated measures ANOVA and multivariable linear regression for differential effects on remnant and LDL cholesterol based upon pretreatment nonfasting triglyceride levels. Results. Remnant cholesterol as well as total, LDL, non-HDL cholesterol, and triglycerides decreased significantly (PP Conclusions. In patients receiving PCSK9 inhibitors, remnant cholesterol as determined from nonfasting blood was reduced in proportion to pretreatment triglycerides.