Preventing Potential Patient Harm Through Clinical Content Interventions During Oncology Clinical Trial Implementation.

OBJECTIVES: Clinical trial documents are complex and may have inconsistencies, leading to potential site implementation errors and may compromise participant safety. This study characterizes the frequency and type of administrative and potential patient safety interventions (PPSIs) made during the review of oncology trial documents for clinical trial implementation by centralized clinical content specialists. METHODS: A dedicated group of centralized clinical content specialists reviewed trial documents, including the protocol, laboratory manual, and pharmacy/cellular therapy manual, and collected intervention data over a 1-year period. Each trial was categorized by study phase and sponsor type, and multiple interventions could be identified per trial. Interventions were deemed administrative or PPSIs, with PPSIs further subcategorized as medication, laboratory, procedure related, or other. RESULTS: Of 585 clinical trials reviewed, 269 (46%) required intervention(s). Among 1001 interventions, 171 (17.1%) were PPSIs. Most PPSIs were medication related (45.6%), with drug dosing interventions most frequently identified (53.8%). Phase 1 trials had the highest proportion of PPSIs (0.35:1) and administrative interventions (2:1) per trial compared with all other phases. Investigator-initiated trials saw the highest proportion of PPSIs per trial (0.44:1) of all sponsor types. CONCLUSIONS: This study demonstrates a gap in patient safety when assessing trial documents for clinical trial implementation. One solution to address this gap is the utilization of a centralized team of clinical specialists to preemptively review trial documents, thereby enhancing patient safety during clinical trial conduct.

Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing.

Pediatric patients with exocrine pancreatic insufficiency (EPI) have symptoms that include abdominal pain, weight loss or poor weight gain, malnutrition, and steatorrhea. This condition can be present at birth or develop during childhood for certain genetic disorders. Cystic fibrosis (CF) is the most prevalent disorder in which patients are screened for EPI; other disorders also are associated with pancreatic dysfunction, such as hereditary pancreatitis, Pearson syndrome, and Shwachman-Diamond syndrome. Understanding the clinical presentation and proposed pathophysiology of the pancreatic dysfunction of these disorders aids in diagnosis and treatment. Testing pancreatic function is challenging. Directly testing aspirates produced from the pancreas after stimulation is considered the gold standard, but the procedures are not standardized or widely available. Instead, indirect tests are often used in diagnosis and monitoring. Although indirect tests are more widely available and easier to perform, they have inherent limitations due to a lack of sensitivity and/or specificity for EPI.

Impact of Unconjugated estriol (uE3) assay interference on prenatal screening tests.

BACKGROUND: Unconjugated estriol (uE3) is an important biomarker in second trimester prenatal screening. Previous studies from our laboratory identified rare interference in the Beckman uE3 assay due to anti-ALP antibodies, which could be mitigated with a scavenger or heat-inactivated ALP (hALP). In the current study, 160 de-identified patient samples previously submitted for the Quad screen with low uE3 multiples of the median (MoM ≤0.50) were investigated for potential interference. METHODS: A reagent pack spiking strategy with hALP was employed to understand if the interference could be identified and mitigated in a scalable manner. The 160 samples were measured using uE3 lot #920861 previously known to be subject to interference, lot #920861 spiked with hALP, and the vendor reformulated lot #922579. Samples were suspected to have interference if the percent difference in uE3 measurements was >50%. Pseudo-risks were calculated using a test patient environment to understand the screening impact due to the change in uE3 result. RESULTS: Seventeen of the 160 samples had uE3 results that were >50% different between the hALP spiked and non-spiked reagent pack. Both original lot #920861 with hALP and reformulated lot #922579 identified the same 17 patients as having interference in lot #920861. Analysis of screening risks using a test patient environment showed that assay interference could result in false positives for one trisomy 21 and three trisomy 18 post-test risk calculations. CONCLUSION: Our experiment of reagent pack spiking with hALP produced similar uE3 results to a reformulated reagent designed to address potential interference, demonstrating that this is a feasible strategy to screen for interference in a scalable manner. The vendor-provided reformulation addressed anti-ALP interference and improved the performance of the screen.

Measurement of Urinary Free Cortisol and Cortisone by LC-MS/MS.

Monitoring urinary free cortisol (UFC) excretion helps assess adrenal function and is used to screen for endogenous Cushing's syndrome caused by an adrenal or pituitary tumor. While serum cortisol levels fluctuate in response to time of day, stress, and concentrations of cortisol-binding globulin (CBG), a 24-h urine collection measures the cortisol produced over the entire day and does not suffer from as much variability as a serum measurement.We describe here a method of measurement of urinary free cortisol (UFC) and cortisone using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Urine samples, combined with stable isotope-labeled internal standards, are extracted by liquid-liquid extraction using ethyl acetate and hexane. An API 5500 mass spectrometer operated in positive atmospheric pressure chemical ionization (APCI) mode is used for detection.

Iatrogenic Cushing syndrome in 24-hour urine free cortisol measurement.

Cushing syndrome (CS) is caused by an excess of glucocorticoids that results in a variety of symptoms such as central obesity, moon facies, hirsutism, and reddish-purple stretch marks. Cortisol is the most potent endogenous glucocorticoid, and measuring the total amount excreted in the urine over a 24-hour period is useful to screen for CS caused by a tumor. However, most cases of CS are believed to be caused by exogenous glucocorticoids, such as prednisone and prednisolone, which are administered for anti-inflammatory and immunosuppressive treatments. This is often referred to as iatrogenic (drug-related or exogenous) CS. We modified an LC-MS/MS method for urine free cortisol to detect the presence of prednisone and prednisolone in patient samples. We wanted to understand the potential prevalence of exogenous CS in our patient population.

Clinical and Analytical Characterization of the DiaSorin and ScheBo Fecal Pancreatic Elastase 1 Assays.

OBJECTIVES: Fecal pancreatic elastase (PE) assays are screening tests for exocrine pancreatic insufficiency (EPI). We analytically evaluated a new PE assay and retrospectively analyzed data from an academic hospital and reference laboratory to understand the clinical utility. METHODS: Forty stool samples with different PE concentrations were tested on the ScheBo enzyme-linked immunosorbent assay (ELISA) versus DiaSorin LIAISON immunoassay; a simple-to-use extraction device was assessed. The cross-reactivity of porcine enzymes was investigated in the immunoassay. Charts of 207 patients with PE results less than 250 µg/g at an academic hospital were reviewed, and data were analyzed for 5136 patients with repeat PE results from a reference laboratory. RESULTS: The LIAISON immunoassay gave comparable results to the ScheBo ELISA, with 87.5% agreement of PE results in classifying as sufficient, mild/moderate insufficiency, or severe insufficiency. The extraction device worked well compared with manual weighing, and no cross reactivity with porcine enzymes was observed. In agreement with prior studies, our clinical data suggested that PE assays were most useful in detecting severe EPI. CONCLUSIONS: The new DiaSorin LIAISON immunoassay preforms similarly to the well-known ScheBo ELISA. Pancreatic elastase assays can help identify patients with severe EPI but are not as useful in classifying mild/moderate EPI.

Comparison of fecal calprotectin and pancreatic elastase assays based on proficiency testing results.

BACKGROUND: Fecal calprotectin and fecal pancreatic elastase assays are not standardized because of a lack of suitable reference material. Laboratories may have difficulty in switching assays because different manufacturers do not compare well with each other despite having similar reference intervals. Data from proficiency testing performed in Germany (Fecal Diagnostics 01 Survey, INSTAND eV) were investigated to understand how results differed across eight calprotectin and five pancreatic elastase manufacturers. METHODS: Data were collected from participating laboratories in external quality assessment schemes from 2015 to 2020 for calprotectin and 2017 to 2020 for pancreatic elastase. The manufacturer group mean values and standard deviations were calculated. Reference points were created for each external quality assessment scheme by calculating the average of all manufacturer group means. Deming regression analyses were used to observe the differences across manufacturers. RESULTS: The slopes of the Deming regression spanned 0.37-1.91 for calprotectin and 0.84-1.33 for pancreatic elastase. The calprotectin assays had a high degree of variability in quantitative results by manufacturer. However, pancreatic elastase assays appear to be harmonized across the different manufacturer when considering the qualitative interpretation. CONCLUSIONS: Both calprotectin and pancreatic elastase assays could be improved by standardization efforts. Given the clinical utility and our data demonstrating high inter-manufacturer variability, calprotectin should be prioritized over pancreatic elastase in standardization efforts.

Comparison of Next-Generation Assays for Fecal Calprotectin vs the PhiCal Assay.

OBJECTIVES: To compare the PhiCal assay (CALPRO), the first US Food and Drug Administration-approved assay for fecal calprotectin, to 4 next-generation assays. METHODS: Stool samples from 50 patients were selected, and relevant clinical information was collected. Comparisons were performed using the PhiCal, fCAL turbo (BÜHLMANN), LIAISON Calprotectin (DiaSorin), QUANTA Lite Calprotectin ELISA (Inova Diagnostics), and Calprotectin Chemiluminescence ELISA (ALPCO) assays. RESULTS: All 4 assays had acceptable agreement with PhiCal when qualitatively categorizing results. Within the PhiCal reportable range of 16 to 1,250 µg/g, the DiaSorin, Inova Diagnostics, and ALPCO assays had Spearman correlation coefficients of 0.98, 0.97, and 0.95 and positive biases of 17%, 20%, and 15%, respectively. The BÜHLMANN assay ran approximately 2-fold higher than the PhiCal assay but had a correlation coefficient of 0.98, with similar result categorization. CONCLUSIONS: Our results demonstrate good comparison between PhiCal and 4 next-generation assays. Laboratories performing fecal calprotectin assays may have compelling reasons to adopt next-generation fecal calprotectin testing, such as greater automation, a decreased number of replicates needed per test, and the use of stool-extraction devices. These benefits could decrease turnaround times and lower costs. Although the results of the assays correlated, they are not standardized. Laboratories adopting the newer assays will need to further investigate their performance through validation studies.

Hereditary pancreatitis in a young adult: Acute to chronic.

This report investigates an unusual case of recurrent pancreatitis. A 22-year-old female was admitted to the emergency room for severe abdominal pain, nausea, and weight loss. She reported having these symptoms since she was a toddler. The clinician ordered fecal pancreatic elastase-1, fat-soluble vitamins, molecular studies, and imaging of the pancreas by computed tomography. The screening test result for fecal pancreatic elastase-1 revealed severe pancreatic exocrine insufficiency, and the concentrations of fat-soluble vitamins were also low. Imaging showed scattered calcifications in the pancreas. These findings supported a diagnosis of chronic pancreatitis. Due to the rarity of chronic pancreatitis in young adults, molecular studies were performed. The patient was found to be homozygous for a mutation in the SPINK1 gene, which is associated with hereditary pancreatitis. This case report discusses hereditary pancreatitis and highlights data on the utilization of fecal pancreatic elastase-1 to assess pancreatic exocrine insufficiency.

Excessively low cholesterol and triglyceride levels in an apparently healthy patient.

Lipid panels are a commonly performed test in clinical laboratories. Due to the high prevalence of cardiovascular diseases around the world, it is common to see serum or plasma specimens with high results for one or more components of the lipid panel. Exceedingly low results, however, are rare and may be attributed to certain genetic, infectious, or autoimmune conditions in addition to analytical interference. Here we report a serum specimen from a 58-year-old female with cholesterol and triglyceride values below the detection limit of the assay, which was investigated to identify the cause of the anomaly. Using vitamin C test strips and high-performance liquid chromatography, the presence of high levels of antioxidant vitamin C in the patient specimen was confirmed. Subsequent treatment of the sample with the enzyme ascorbate oxidase inactivated vitamin C, leading to lipid analyte values falling within the expected range upon repeat analysis. Thus, analytical interference by vitamin C should be considered when suspiciously low lipid panel results are encountered.

Retrospective comparison of results for simultaneous orders for LDL particle count, apolipoprotein B, and LDL-C.

BACKGROUND: Analysis of lipoprotein size and composition by nuclear magnetic resonance (NMR) has been advocated as a method for identifying individuals at high CVD risk. We compared risk stratification between NMR-based LDL particle number (LDL-PNUM), LDL-cholesterol (LDL-C), and apolipoprotein B (apoB). METHODS: Retrospective data from patients with simultaneous orders for LDL-PNUM, LDL-C, and apoB were analyzed and included data from an NMR assay (Numares). Quantitative and qualitative analyses were performed. Additional lipid parameters were investigated for patients with discordant risk classifications in LDL-related measurements. The percent change of LDL-PNUM was compared to the percent change of LDL-C or apoB for patients with serial measurements. RESULTS: We observed good quantitative and qualitative correlation when comparing LDL-PNUM to either LDL-C or apoB (Spearman's ρ ≥ 0.83, percent agreements ≥ 85%). Among the patients with discordant risk stratification, most had increased LDL-PNUM and normal LDL-C and apoB. For patients with serial measurements, a strong correlation between the LDL-PNUM percent change and the LDL-C or apoB percent change was observed (Spearman's ρ > 0.93). CONCLUSION: For many patients, risk stratification of LDL-PNUM is similar to apoB or LDL-C using cut-offs proposed by guidelines.

Clinical and Analytical Verification of an Automated Fecal Calprotectin Immunoassay with Extraction Device.

BACKGROUND: Fecal calprotectin (FC) is a screening test for intestinal inflammation, and often used by clinicians to help identify and monitor patients with inflammatory bowel disease (IBD). Improvements in FC assays include moving to more automated immunoassays compared to ELISAs and simple-to-use extraction devices compared to manual weighing for the extraction process. METHODS: A method comparison was performed between the PhiCal ELISA and LIAISON immunoassay for 53 stool samples, and the screening results were compared to the gold standard endoscopy with biopsy results. Clinical accuracy was assessed by comparing the FC results from each assay to the presence or absence of inflammation determined from the biopsy report. The performance of the extraction device was compared to manually weighing. Additional studies were completed to verify the manufacturer's claims. RESULTS: The FC results were compared to the biopsy results for detecting inflammation. PhiCal ELISA had a sensitivity of 86% and specificity of 100%, while the LIAISON immunoassay had a sensitivity of 97% with specificity of 94%. Therefore, the LIAISON immunoassay performed better than the PhiCal ELISA. The extraction device performed well compared to manual weighing if stool samples were <800 µg/g, within Bristol stool types 2-6, and did not contain a significant amount of undigested material, fibrous material, or mucus. CONCLUSION: The LIAISON immunoassay with extraction device has acceptable performance for clinical use in measuring fecal calprotectin.

Are calprotectin and lactoferrin equivalent screening tests for inflammatory bowel disease?

BACKGROUND: Lactoferrin and calprotectin are frequently ordered stool tests used to screen patients for inflammatory bowel disease versus functional bowel disease. Current guidelines recommend using either one to screen for inflammation in the GI tract; however, little information is available on how these 2 assays compare and their use in different clinical specialties. METHODS: We compared order patterns for lactoferrin and calprotectin using data from a large reference laboratory over a 10-y period (2009-2019). We also studied the concordance of lactoferrin and calprotectin in cases where both tests were ordered concurrently. Finally, we reviewed the records at a university hospital to determine which clinicians ordered each test and the indications associated with orders. RESULTS: Orders for calprotectin are increasing relative to lactoferrin. The relative proportion of calprotectin orders have increased from 60% to nearly 90% over the past decade. Results for lactoferrin and calprotectin show concordance (90%). Calprotectin and lactoferrin are ordered by different clinical specialties for different indications. Calprotectin is most often ordered by gastroenterologists in the context of abdominal pain. Lactoferrin is most often ordered by primary care providers in the context of acute diarrhea. CONCLUSION: Lactoferrin and calprotectin are not treated as equivalent tests by clinicians.

Can fecal calprotectin serve as a screen for necrotizing enterocolitis in infants?

BACKGROUND: Researchers are debating if fecal calprotectin results are useful for infant patients, especially in screening for necrotizing enterocolitis (NEC). Currently, none of the FDA-approved calprotectin assays provide a cut-off for infant patients. We retrospectively analyzed data from a reference laboratory and university hospital to investigate if a cut-off could be established for infant patients. METHODS: Data from a national reference laboratory of 5144 test results for fecal calprotectin were analyzed for infant patients, and a cut-off was estimated based on the distribution of results. Additionally, a literature proposed cut-off of 226 µg/g was also considered. Validation of either cut-off was attempted by review of the electronic medical record of our university hospital for 110 infant patients with results for fecal calprotectin. RESULTS: Infants had a high percentage of elevated fecal calprotectin results when using the adult cut-offs set by the manufacturer. A cut-off of 247 µg/g was estimated based on the reference laboratory results for infants 0-2 months old, which is similar to a literature proposed cut-off of 226 µg/g. However, the positive predictive value (PPV) for both cut-offs was <0.6 when retrospectively analyzing data from a university hospital. CONCLUSION: Due to the low PPVs, the two infant-specific cut-offs for fecal calprotectin would not be useful to screen for NEC in infants at our university hospital.

Stool Reducing Sugars and Stool pH Are Poor Screening Tests for Intestinal Disaccharidase Deficiencies in Children.

BACKGROUND: Tests for stool reducing sugars and stool pH are ordered for children with osmotic diarrhea to screen for carbohydrate malabsorption. METHODS: We compared the results of the two screening tests, stool reducing sugars and stool pH, with a more definitive result from an intestinal tissue disaccharidase activity assay ordered for pediatric patients (<18 years old). Overall, 159 patients had results for tissue disaccharidase and stool reducing sugars, but only 115 had additional results of stool pH. Forty-six of the 159 patients had mild, moderate, or severe disaccharidase deficiencies. The sensitivity and specificity of the screening tests were calculated for individual disaccharidase deficiencies. In addition, trends of abnormal tissue disaccharidase, stool reducing sugars, and stool pH results were examined in different age groups. RESULTS: The sensitivities for stool reducing sugars and stool pH were 9% to 28% and specificities were 74% to 81% for individual disaccharidase deficiencies. Infants (0 years of age) had the highest percentage of abnormal results across all three tests; however, the positive predicative values were 54% and 50% for stool reducing sugars and stool pH, respectively. CONCLUSIONS: The screening tests, stool reducing sugars and stool pH, had low sensitivity compared with results of measured tissue disaccharidase activity in pediatric patients. Infants had the highest percentage of abnormal results for all three tests, but the screening tests still performed poorly in that age group. This study suggests that stool reducing sugars and stool pH should not be used as screening tests for carbohydrate malabsorption due to disaccharidase deficiencies in pediatric patients.

Bad Tests Die Slowly: The Myelin Basic Protein Example.

BACKGROUND: Our national reference laboratory sought to improve stewardship for multiple sclerosis (MS) testing, which included orders for myelin basic protein (MBP) and oligoclonal bands (OCB). From 2011 to 2012, we performed 2 interventions for MS testing: one gentle-strength intervention of a publication designed to educate others about the lack of utility for MBP results and a second medium-strength intervention that included removal of MBP from the panel of MS tests. The ordering trends and practice variation were examined for OCB and MBP to retrospectively observe the effect of the interventions. METHODS: Data from clients within academic and community hospitals were examined (n = 1710 clients). Ordering patterns for OCB and MBP were investigated from 2008 to 2018 by calculating the %OCB: %OCB = (OCB)/(OCB + MBP). Practice variation was examined by comparing the distribution of clients with different %OCB statistics before and after the interventions in 5-year blocks (2008-2012 vs 2014-2018). RESULTS: From 2000 to 2011, the %OCB was approximately 50%, but gradually increased to 67% in 2018. For practice variation, analysis of the distribution of clients by %OCB also demonstrated a shift toward clients favoring OCB alone vs OCB + MBP for MS testing for the later time period of 2014-2018. CONCLUSION: Our 2 interventions had a measurable, beneficial effect on ordering trends for MS testing over a 10-year period at a single reference laboratory. However, given that MBP has questionable clinical utility, stronger interventions are likely needed to bring about larger changes in ordering behavior.

End of the line for fetal lung maturity testing.

OBJECTIVE: During the last decade, guidelines published by the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal Fetal Medicine (SMFM) have emphasized an increasingly limited role for fetal lung maturity (FLM) testing. As a reference laboratory for FLM testing, we were therefore interested in determining the impact of changing guidelines on our test volumes. METHODS: We retrospectively reviewed FLM test volume data from 2006 to 2016 for the following FLM assays: lecithin/sphingomyelin ratio, phosphatidylglycerol, disaturated lecithin, and lamellar body count. RESULTS: We found that there was a precipitous decline in test volumes from 2006 to 2016; our analysis led us to discontinue providing reference laboratory FLM testing in 2016 given the very low volumes. CONCLUSIONS: The 2019 ACOG guidelines now state that FLM testing no longer has clinical utility. Therefore, clinical laboratory directors should meet with obstetrics providers to discuss discontinuation of FLM testing at their institutions.

Analysis of vitamin levels and deficiencies in bariatric surgery patients: a single-institutional analysis.

BACKGROUND: Bariatric surgery patients are at risk for vitamin deficiencies. OBJECTIVES: Investigate the prevalence of deficiencies of vitamins A, B1, B12, D, and folate in sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) patients in a single institution. SETTING: An academic medical center. METHODS: Retrospective chart reviews of 468 bariatric surgery patients (358 SG and 110 RYGB) were analyzed for vitamin levels, calcium, and parathyroid hormone. Both preoperative and postoperative measurements were obtained. RESULTS: Deficiency of vitamin D was the most common, seen in 27% preoperatively. Postoperatively, RYGB patients had a higher prevalence of vitamin D deficiency than SG patients (11.5% RYGB versus 5.2% SG within the first postoperative year, and 20.3% RYGB versus 13.4% SG after 1 year). Elevated parathyroid hormone was observed in 45% of RYGB patients after 1 year postoperatively. Vitamin A deficiency was uncommon preoperatively (2.7% SG versus 1.7% RYGB), but increased after surgery (9.4% SG versus 15.9% RYGB within 1 year postoperatively, and 5.2% SG versus 7.7% RYGB after 1 year). Vitamin B1 deficiency was observed in 8.1% SG versus 1.7% RYGB patients preoperatively and increased during the first year postoperatively (SG 10.5% and RYGB 13.7%), but improved after 1 year (7.2% SG versus 5.9% RYGB). Less than 2% of Vitamin B12 deficiencies and no folate deficiencies occurred in both SG and RYGB patients. CONCLUSIONS: The highest prevalence of vitamin B1 and A deficiencies were seen in the first year postoperatively. Vitamin B12 and folate deficiency were uncommon in our patients. Vitamin D deficiency improved after surgery, but elevated parathyroid hormone was common after RYGB.

Evaluation of LeadCare Ultra® as an initial screen for elevated blood lead levels.

OBJECTIVE: The LeadCare Ultra® (LCU) was compared to inductively coupled plasma mass spectrometry ICP-MS for use as a screening test for elevated blood lead levels (BLLs) in capillary samples from children. METHODS: During the validation, method comparisons between LCU and ICP-MS were analyzed to determine the bias above, near, and below the BLL cut-off of 5 µg/dL. Additionally, capillary samples that screened positive by LCU (above the 5 µg/dL cut-off) were compared to venous samples analyzed by ICP-MS for confirmatory testing. RESULTS: LCU had a positive bias (1.7 µg/dL) below the cut-off of BLL <5 µg/dL, no bias near the cut-off from BLL 5-10 µg/dL, and a negative bias (-0.8 µg/dL) for BLL >10 µg/dL compared to ICP-MS. Of the 59 capillary samples that screened positive by LCU between May of 2017 to April of 2018, 19 were confirmed positive by ICP-MS, 30 were confirmed negative by ICP-MS, and 10 did not have a confirmed result. CONCLUSION: The LCU assay is an acceptable screen for capillary samples with the BLL cut-off of 5 µg/dL.