Automating the Detection of IV Fluid Contamination Using Unsupervised Machine Learning.

BACKGROUND: Intravenous (IV) fluid contamination is a common cause of preanalytical error that can delay or misguide treatment decisions, leading to patient harm. Current approaches for detecting contamination rely on delta checks, which require a prior result, or manual technologist intervention, which is inefficient and vulnerable to human error. Supervised machine learning may provide a means to detect contamination, but its implementation is hindered by its reliance on expert-labeled training data. An automated approach that is accurate, reproducible, and practical is needed. METHODS: A total of 25 747 291 basic metabolic panel (BMP) results from 312 721 patients were obtained from the laboratory information system (LIS). A Uniform Manifold Approximation and Projection (UMAP) model was trained and tested using a combination of real patient data and simulated IV fluid contamination. To provide an objective metric for classification, an "enrichment score" was derived and its performance assessed. Our current workflow was compared to UMAP predictions using expert chart review. RESULTS: UMAP embeddings from real patient results demonstrated outliers suspicious for IV fluid contamination when compared with the simulated contamination's embeddings. At a flag rate of 3 per 1000 results, the positive predictive value (PPV) was adjudicated to be 0.78 from 100 consecutive positive predictions. Of these, 58 were previously undetected by our current clinical workflows, with 49 BMPs displaying a total of 56 critical results. CONCLUSIONS: Accurate and automatable detection of IV fluid contamination in BMP results is achievable without curating expertly labeled training data.

Utility of Commercially Available Quantitative hCG Immunoassays as Tumor Markers in Trophoblastic and Non-Trophoblastic Disease.

BACKGROUND: The use of quantitative human chorionic gonadotropin (hCG) as a tumor marker is widely accepted despite lack of FDA-approval for oncology. Differences in iso- and glycoform recognition among hCG immunoassays is well established, exhibiting wide inter-method variability. Here, we assess the utility of 5 quantitative hCG immunoassays for use as tumor markers in trophoblastic and non-trophoblastic disease. METHODS: Remnant specimens were obtained from 150 patients with gestational trophoblastic disease (GTD), germ cell tumors (GCT), or other malignancies. Specimens were identified by review of results from physician-ordered hCG and tumor marker testing. Five analyzer platforms were used for split specimen analysis of hCG: Abbott Architect Total, Roche cobas STAT, Roche cobas Total, Siemens Dimension Vista Total, and Beckman Access Total. RESULTS: Frequency of elevated hCG concentrations (above reference cutoffs) was highest in GTD (100%), followed by GCT (55% to 57%), and other malignancies (8% to 23%). Overall, the Roche cobas Total detected elevated hCG in the greatest number of specimens (63/150). Detection of elevated hCG in trophoblastic disease was nearly equivalent among all immunoassays (range, 41 to 42/60). CONCLUSIONS: While no immunoassay is likely to be perfect in all clinical situations, results for the 5 hCG immunoassays evaluated suggest that all are adequate for use of hCG as a tumor marker in gestational trophoblastic disease and select germ cell tumors. Further harmonization of hCG methods is needed as serial testing for biochemical tumor monitoring must still be performed using a single method. Additional studies are needed to assess the utility of quantitative hCG as a tumor marker in other malignant disease.

Evaluation of Radioactivity in Patient Specimens Received in the Core Laboratory at a National Cancer Institute (NCI) Designated Cancer Center.

BACKGROUND: Biological specimens from patients who have received radiopharmaceuticals are often collected for diagnostic testing and sent to clinical laboratories. Residual radiation has long been assumed to be minimal. However, literature is sparse and may not represent the specimen volumes or spectrum of radionuclides currently seen at National Cancer Institute (NCI)-designated cancer centers. This study examined the radiopharmaceuticals associated with patient specimens received in the hospital core laboratory and assessed the potential risk of external radiation exposure to laboratory personnel. METHODS: The types and amounts of radiopharmaceuticals administered in a large metropolitan hospital system were retrospectively examined over a 20-month study period. The associated biological specimens sent to the largest core laboratory in the system for testing were evaluated. In addition, manual survey meter assessment of random clinical specimens and weekly wipe tests were performed for 44 weeks, and wearable and environmental dosimeters were placed for 6 months. RESULTS: Over 11 000 specimens, collected within 5 physical half-lives of radiopharmaceutical administration, were processed by our laboratory. Manual survey meter assessment of random clinical specimens routinely identified radioactive specimens. If held in a closed palm for >2 min, many samples could potentially deliver a 0.02 mSv effective dose of radiation. CONCLUSIONS: The laboratory regularly receives radioactive patient specimens without radioactive labels. Although the vast majority of these are blood specimens associated with low-dose diagnostic radiopharmaceuticals, some samples may be capable of delivering a significant amount of radiation. Recommendations for laboratories associated with NCI cancer centers are given.

Evaluation of the Risk of Laboratory Microbial Contamination during Routine Testing in Automated Clinical Chemistry and Microbiology Laboratories.

BACKGROUND: Every clinical specimen is potentially infectious, but data regarding risk for contamination of the laboratory environment during routine testing are scarce. We assessed contamination during routine sample analysis in automated clinical chemistry and microbiology laboratories. METHODS: A fluorescent marker was applied to specimen container exteriors to assess the impact of gross contamination. Nonpathogenic MS2 virus was added to remnant blood, urine, and ESwab matrices as a biomarker of cross-contamination. Samples were processed and analyzed using Roche Cobas 8100 and ISE, c502, e602, and c702 modules (blood) and BD Kiestra total laboratory automation (blood, urine, ESwabs) over 3 experiments. Fluorescence transfer to laboratory surfaces and personnel was visualized using ultraviolet light. Surfaces were swabbed and assessed for MS2 cross-contamination by RT-PCR. Adherence to standard precautions by laboratory staff was assessed by observation. RESULTS: Fluorescence was observed on 49 of 165 (30%) laboratory surfaces and personnel and 21 of 93 (23%) total laboratory automation instruments. Fluorescence transferred most frequently to gloves (31/40), computer accessories (9/18), and specimen loading racks (12/12). None of 123 areas swabbed were positive for MS2. Improper personal protective equipment use occurred at a rate of 0.36 and 0.15 events per staff per hour in the chemistry and microbiology laboratories, respectively. Hand-washing compliance was observed for 61 of 132 (46%) staff members evaluated. CONCLUSIONS: Analysis of grossly contaminated specimens on automated chemistry and microbiology equipment elicits a low likelihood of instrument contamination. However, handling contaminated specimen containers can result in contamination of environmental laboratory surfaces, representing a source of risk that is heightened by low adherence to appropriate personal protective equipment.

Clinical Performance of Two SARS-CoV-2 Serologic Assays.

BACKGROUND: The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a rapid proliferation of serologic assays. However, little is known about their clinical performance. Here, we compared two commercial SARS-CoV-2 IgG assays. METHODS: 103 specimens from 48 patients with PCR-confirmed SARS-CoV-2 infections and 153 control specimens were analyzed using SARS-CoV-2 serologic assays by Abbott and EUROIMMUN (EI). Duration from symptom onset was determined by medical record review. Diagnostic sensitivity, specificity, and concordance were calculated. RESULTS: The Abbott SARS-CoV-2 assay had a diagnostic specificity of 99.4% (95% CI; 96.41-99.98%), and sensitivity of 0.0% (95% CI; 0.00-26.47%) at <3 days post symptom onset, 30.0% (95% CI; 11.89-54.28) at 3-7d, 47.8% (95% CI; 26.82-69.41) at 8-13d and 93.8% (95% CI; 82.80-98.69) at ≥14d. Diagnostic specificity on the EI assay was 94.8% (95% CI; 89.96-97.72) if borderline results were considered positive and 96.7% (95% CI; 92.54-98.93) if borderline results were considered negative. The diagnostic sensitivity was 0.0% (95% CI; 0.00-26.47%) at <3d, 25.0% (95% CI; 8.66-49.10) at 3-7d, 56.5% (95% CI; 34.49-76.81) at 3-7d and 85.4% (95% CI; 72.24-93.93) at ≥14d if borderline results were considered positive. The qualitative concordance between the assays was 0.83 (95% CI; 0.75-0.91). CONCLUSION: The Abbott SARS-CoV-2 assay had fewer false positive and false negative results than the EI assay. However, diagnostic sensitivity was poor in both assays during the first 14 days of symptoms.

Association between SARS-CoV-2 Neutralizing Antibodies and Commercial Serological Assays.

BACKGROUND: Commercially available SARS-CoV-2 serological assays based on different viral antigens have been approved for the qualitative determination of anti-SARS-CoV-2 antibodies. However, there are limited published data associating the results from commercial assays with neutralizing antibodies. METHODS: Sixty-six specimens from 48 patients with PCR-confirmed COVID-19 and a positive result by the Roche Elecsys Anti-SARS-CoV-2, Abbott SARS-CoV-2 IgG, or EUROIMMUN SARS-CoV-2 IgG assays and 5 control specimens were analyzed for the presence of neutralizing antibodies to SARS-CoV-2. Correlation, concordance, positive percent agreement (PPA), and negative percent agreement (NPA) were calculated at several cutoffs. Results were compared in patients categorized by clinical outcomes. RESULTS: The correlation between SARS-CoV-2 neutralizing titer (EC50) and the Roche, Abbott, and EUROIMMUN assays was 0.29, 0.47, and 0.46, respectively. At an EC50 of 1:32, the concordance kappa with Roche was 0.49 (95% CI; 0.23-0.75), with Abbott was 0.52 (0.28-0.77), and with EUROIMMUN was 0.61 (0.4-0.82). At the same neutralizing titer, the PPA and NPA for the Roche was 100% (94-100) and 56% (30-80); Abbott was 96% (88-99) and 69% (44-86); and EUROIMMUN was 91% (80-96) and 81% (57-93) for distinguishing neutralizing antibodies. Patients who were intubated, had cardiac injury, or acute kidney injury from COVID-19 infection had higher neutralizing titers relative to those with mild symptoms. CONCLUSIONS: COVID-19 patients generate an antibody response to multiple viral proteins such that the calibrator ratios on the Roche, Abbott, and EUROIMMUN assays are all associated with SARS-CoV-2 neutralization. Nevertheless, commercial serological assays have poor NPA for SARS-CoV-2 neutralization, making them imperfect proxies for neutralization.

Clinical Performance of the BioPlex 2200 Syphilis Total & RPR Assay at a Tertiary Medical Center with a High Rate of Syphilis.

Manual treponemal and nontreponemal serologic testing has historically been used for the diagnosis of syphilis. This approach is simple and reproducible but labor intensive. Recently, the FDA cleared the fully automated BioPlex 2200 Syphilis Total & RPR assay for the detection of treponemal and nontreponemal antibodies. We evaluated the clinical performance of this assay at a tertiary medical center with a high syphilis prevalence. Prospective consecutively collected (n = 400) and known RPR-positive (n = 100) specimens were compared using predicate manual rapid plasma reagin (RPR) and fluorescent treponemal antibody absorption (FTA) methods and the BioPlex 2200 Syphilis Total & RPR assay. Positive and negative percent agreements (PPA and NPA, respectively) between the assays were calculated. The PPA and NPA between the manual and BioPlex 2200 RPR results for the prospective population were 85% (17/20; 95% confidence interval [CI], 69% to 100%) and 98% (373/380; 95% CI, 97% to 99%), respectively. The PPA for the manual RPR-positive population was 88% (88/100; 95% CI, 82% to 94%). Overall, the manual and BioPlex 2200 RPR titers demonstrated 78% (99/127) concordance within ±1 dilution and 94% (120/127) within ±2 dilutions. An interpretation of the syphilis serologic profile using the traditional algorithm showed a concordance of 99.5% in the prospective population and 85% in the manual RPR-positive cohort. The performance of the BioPlex 2200 Syphilis Total & RPR assay is comparable to those of manual methods. The high NPA of this assay combined with the ability to automate a historically labor-intensive assay is an appealing attribute for syphilis screening in a high-volume laboratory.

Ethics for Laboratory Medicine.

BACKGROUND: Laboratory medicine, like other areas of medicine, is obliged to adhere to high ethical standards. There are particular ethical issues that are unique to laboratory medicine and other areas in which ethical issues uniquely impact laboratory practice. Despite this, there is variability in ethics education within the profession. This review provides a foundation for the study of ethics within laboratory medicine. CONTENT: The Belmont Report identifies 3 core principles in biomedical ethics: respect for persons (including autonomy), beneficence (and its corollary nonmalfeasance), and justice. These core principles must be adhered to in laboratory medicine. Informed consent is vital to maintain patient autonomy. However, balancing patient autonomy with the desire for beneficence can sometimes be difficult when patients refuse testing or treatment. The use of leftover or banked samples is fundamental to the ability to do research, create reference intervals, and develop new tests, but it creates problems with consent. Advances in genetic testing have created unique ethical issues regarding privacy, incidental findings, and informed consent. As in other professions, the emergence of highly contagious and deadly infectious diseases poses a difficult ethical dilemma of helping patients while protecting healthcare workers. CONCLUSIONS: Although many clinical laboratorians do not see or treat patients, they must be held accountable to the highest ethical and professional behavior. Recognition and understanding of ethical issues are essential to ethical practice of laboratory medicine.

Parameters for Validating a Hospital Pneumatic Tube System.

BACKGROUND: Pneumatic tube systems (PTSs) provide rapid transport of patient blood samples, but physical stress of PTS transport can damage blood cells and alter test results. Despite this knowledge, there is limited information on how to validate a hospital PTS. METHODS: We compared 2 accelerometers and evaluated multiple PTS routes. Variabilities in PTS forces over the same routes were assessed. Response curves that demonstrate the relationship between the number and magnitude of accelerations on plasma lactate dehydrogenase (LD), hemolysis index, and potassium in PTS-transported blood from volunteers were generated. Extrapolations from these relationships were used to predict PTS routes that may be prone to false laboratory results. Historical data and prospective patient studies were compared with predicted effects. RESULTS: The maximum recorded g-force was 10g for the smartphone and 22g for the data logger. There was considerable day-to-day variation in the magnitude of accelerations (CV, 4%-39%) within a single route. The linear relationship between LD and accelerations within the PTS revealed 2 PTS routes predicted to increase LD by ≥20%. The predicted increase in LD was similar to that observed in patient results when using that PTS route. CONCLUSIONS: Hospital PTSs can be validated by documenting the relationship between the concentrations of analytes in plasma, such as LD, with PTS forces recorded by 3-axis accelerometers. Implementation of this method for PTS validation is relatively inexpensive, simple, and robust.

Screening method to evaluate point-of-care human chorionic gonadotropin (hCG) devices for susceptibility to the hook effect by hCG ß core fragment: evaluation of 11 devices.

BACKGROUND: The predominant hCG variant in urine, hCG ß core fragment (hCGßcf), has been demonstrated to cause false-negative results in qualitative point-of-care (POC) hCG devices. This is a major concern for healthcare professionals using POC pregnancy tests. We developed a screening method to evaluate qualitative POC hCG devices for their susceptibility to inhibition by hCGßcf. Using this method, we evaluated the performance of 11 commonly used devices. METHODS: A wide range of purified hCG and hCGßcf concentrations were mixed and tested on 2 POC devices. By use of those results, a screening method was defined and 9 additional POC devices were evaluated. Two solutions containing (a) 500 pmol/L (171 IU/L) intact hCG with 0 pmol/L hCGßcf and (b) 500 pmol/L intact hCG with 500 000 pmol/L hCGßcf were used to screen all POC devices. RESULTS: The OSOM and Cen-Med Elite devices were found to be most susceptible to false-negative results due to hCGßcf. The BC Icon 20 and the Alere were the least susceptible. The remaining 7 were moderately affected. Devices that gave the strongest signal with hCGßcf alone were those that were least likely to show a hook effect. CONCLUSIONS: The screening method put forth here can be used by device users and manufacturers to evaluate POC devices for inhibition by hCGßcf. Of 11 devices evaluated, only 2 have been identified that exhibit minimal to no susceptibility to hCGßcf.