Comparing Clinician Estimates versus a Statistical Tool for Predicting Risk of Death within 45 Days of Admission for Cancer Patients.

OBJECTIVES: While clinical practice guidelines recommend that oncologists discuss goals of care with patients who have advanced cancer, it is estimated that less than 20% of individuals admitted to the hospital with high-risk cancers have end-of-life discussions with their providers. While there has been interest in developing models for mortality prediction to trigger such discussions, few studies have compared how such models compare with clinical judgment to determine a patient's mortality risk. METHODS: This study is a prospective analysis of 1,069 solid tumor medical oncology hospital admissions (n = 911 unique patients) from February 7 to June 7, 2022, at Memorial Sloan Kettering Cancer Center. Electronic surveys were sent to hospitalists, advanced practice providers, and medical oncologists the first afternoon following a hospital admission and they were asked to estimate the probability that the patient would die within 45 days. Provider estimates of mortality were compared with those from a predictive model developed using a supervised machine learning methodology, and incorporated routine laboratory, demographic, biometric, and admission data. Area under the receiver operating characteristic curve (AUC), calibration and decision curves were compared between clinician estimates and the model predictions. RESULTS: Within 45 days following hospital admission, 229 (25%) of 911 patients died. The model performed better than the clinician estimates (AUC 0.834 vs. 0.753, p < 0.0001). Integrating clinician predictions with the model's estimates further increased the AUC to 0.853 (p < 0.0001). Clinicians overestimated risk whereas the model was extremely well-calibrated. The model demonstrated net benefit over a wide range of threshold probabilities. CONCLUSION: The inpatient prognosis at admission model is a robust tool to assist clinical providers in evaluating mortality risk, and it has recently been implemented in the electronic medical record at our institution to improve end-of-life care planning for hospitalized cancer patients.

The Impact of Hemolysis-Index Thresholds on Plasma and Serum Potassium Measurements.

BACKGROUND: Modern clinical laboratory analyzers measure a hemolysis index (H-index) because test results can be inaccurate when intracellular contents from erythrocytes leak into serum or plasma. In 2020, Roche Diagnostics decreased the H-index from 90/100 to 20 for potassium, recommending that laboratories avoid using specimens with an H-index >20; however, there are a limited number of studies investigating the impact of this recommendation on patient testing. METHODS: Out of 113 916 serum or plasma potassium tests performed within a 6-month interval, 72 patients with potentially hemolyzed potassium specimens (H-index >20) and a second non-hemolyzed specimen (H-index ≤20) within 2 h were identified. The clinical impact of decreasing the H-index and the utility of applying a corrective formula for adjusting potassium results were evaluated. RESULTS: The majority of initial test results either had small differences between original and corrected results that would not have affected clinical management or H-indices above the threshold previously recommended by Roche. We estimated the second sample was reported an average of 3 h 23 min after the initial sample was collected, with 95% CI [2 h 37 min to 4 h 8 min], and the median time delay was 2 h 44 min. CONCLUSIONS: Our analysis does not show a clear benefit from avoiding the use of potassium specimens above an H-index threshold of 20. Our findings suggest these practices may be detrimental in terms of patient safety due to increased turnaround time for a critical analyte.

False-Negative Urine Human Chorionic Gonadotropin Testing in the Clinical Laboratory.

BACKGROUND: Human chorionic gonadotropin (hCG) assays are used to detect pregnancy, and urine point-of-care tests are frequently used to triage patients. Under certain conditions, urine tests can fail to detect pregnancy, which can have serious consequences for patient management. OBJECTIVES: To understand the prevalence of different factors contributing to false-negative urinary hCG testing results at our institution. METHODS: Clinical data for patients with negative urine hCG results and subsequent positive or equivocal serum hCG results within a 1-year period were reviewed. RESULTS: Out of 9447 negative urine hCG results, 11 potential missed diagnoses were identified, with early gestational age as the most common factor, followed by ß-core hook effects. CONCLUSIONS: Although false-negative urine hCG test results are rare, understanding the commonly encountered reasons for inaccurate testing results can help clinical centers develop strategies to minimize risk for patients.

SIRT1 deacetylase in aging-induced neuromuscular degeneration and amyotrophic lateral sclerosis.

SIRT1 is an NAD+ -dependent deacetylase that functions in a variety of cells and tissues to mitigate age-associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild-type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end-stage disease in high copy SOD1G93A mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.

Lupus anticoagulant testing using two parallel methods detects additional cases and predicts persistent positivity.

BACKGROUND: Antiphospholipid antibody syndrome (APS) is characterized by laboratory evidence of antiphospholipid antibodies (aPL) [e.g. lupus anticoagulant (LA), anticardiolipin (ACL), and/or antiß2-glycoprotein I (aB2GPI)] in a clinical setting of thrombosis or pregnancy morbidity. The International Society on Thrombosis and Haemostasis recommends two different testing modalities to detect LA. To evaluate these recommendations in a clinical setting, our hospital, a tertiary care center with a specialized coagulation laboratory, added the dilute Russell's viper venom time to be performed in parallel with the PTT-lupus anticoagulant to detect LA. METHODS: Results of aPL testing were collected on all patients who had LA testing for one year. Chart review was performed to correlate LA results with ACL, aB2GPI, and clinical history. RESULTS: Patients who were initially LA positive by both PTT-lupus anticoagulant and dilute Russell's viper venom time were more likely to be persistently positive. Patients who were positive for ACL and aB2GPI were likely to be positive by both LA methodologies. No single method was absolutely sensitive, as cases of APS were detected by PTTLA only, DRVVT only, and both methods. CONCLUSIONS: The addition of a second testing method for LA provides additional diagnostic information and may be helpful in stratifying risk of thrombosis.

An improved algorithm for activated protein C resistance and factor V Leiden screening.

OBJECTIVES: To evaluate the performance of a Russell viper venom-based activated protein C resistance (APCR) screening test relative to DNA analysis for the factor V Leiden mutation. METHODS: We evaluated the concordance between Pefakit APCR screening results and DNA analysis for 435 patients homozygous (n = 11), heterozygous (n = 310), or wild-type (n =114) for the G1691A allele. RESULTS: Using receiver operating characteristic analysis, we found that a cutoff of 1.89 for the APCR ratio yields a sensitivity and specificity of 99.1%. In patients with discrepant genotype-phenotype correlation, their APCR may provide a more clinically relevant result. CONCLUSIONS: We compared several strategies for employing reflex testing and found that performing initial APCR screening followed by confirmatory molecular analysis on a subset of cases in the borderline regions between the diagnostic groups can reduce unnecessary testing by approximately 80% without compromising diagnostic accuracy.

A Luminex assay detects amyloid ß oligomers in Alzheimer's disease cerebrospinal fluid.

Amyloid beta (aß) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer's disease (AD) and there is increasing evidence that soluble aß oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased aß42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric aß in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized aß42 and sAPPα fragments. We evaluated oligomeric aß reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and aß42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated aß oligomers compared to control subjects (p < 0.05) and the ratio of aß oligomers to aß42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric aß becomes a routine diagnostic assay for the evaluation of late onset AD patients.

Sirtuin deacetylases in neurodegenerative diseases of aging.

Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid ß (Aß)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. METHODS: The program is open for laboratories using commercially available kits for Aß, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. RESULTS: Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aß-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aß triplex (AßN-42, AßN-40, and AßN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. CONCLUSIONS: Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

Comparison of Russell viper venom-based and activated partial thromboplastin time-based screening assays for resistance to activated protein C.

Thrombotic disease is a significant cause of mortality and morbidity, with an estimated lifetime risk of greater than 10% in Western populations. One of the most common hereditary thrombophilias is the factor V Leiden mutation, which is identified with a screening assay for activated protein C (APC) resistance and confirmed by DNA analysis. In this study, we compared the commercially available Pefakit (Pentapharm, Basel, Switzerland) and Cryocheck (Precision BioLogic, Dartmouth, Canada) assays, 2 recently developed Russell viper venom (RVV)-based screening tests, with the activated partial thromboplastin time (aPTT)-based screening test currently used in our hospital's clinical laboratory. We found that the aPTT-based assay for resistance to APC had a sensitivity of 100%, a specificity of 70%, and a positive predictive value (PPV) of 70%, whereas both of the RVV-based assays exhibited high sensitivity, specificity, and PPV at 100%. In addition, we found that these new functional assays are more cost-effective relative to the screening algorithm previously used in our clinical laboratory and could potentially eliminate the need for DNA analysis, although further study is required.