Improving Assessment of Adherence Behaviors and Drivers: Targeted Literature Review and Concept Elicitation Interviews in Multiple Countries and Disease Populations.

Purpose: Medication adherence is crucial for achieving clinical goals. Medication adherence drivers and behaviors were explored across multiple conditions, countries, and medication schedules/modalities to develop a conceptual model of medication adherence, which could later be used to support development of a patient-reported outcome (PRO) measure of adherence. Patients and Methods: Targeted review of qualitative literature identified important medication adherence concepts. Fifty-seven qualitative concept elicitation interviews were conducted (USA n=21, Spain n=18, Germany n=18). Participants were prescribed medication for: hypertension (n=9), asthma (n=8), multiple myeloma (n=8), psoriasis (n=8), diabetes (n=7), depression (n=7), multiple sclerosis (n=7), and/or schizophrenia (n=6). Thematic analysis of verbatim transcripts was performed. Expert clinicians (n=3) provided input throughout. Results: Nine qualitative articles were selected for review from 2168 screened abstracts. Forty-two medication adherence concepts were reported and grouped into 10 domains. Eight forms of medication adherence were reported during interviews, along with 27 drivers of non-adherence, all of which were incorporated into a conceptual model. Participants reported skipping medication doses (n=36/57; 63.2%) or taking medication later in the day than prescribed (n=29/57; 50.9%). Common drivers of non-adherence included forgetfulness (n=35/57; 61.4%), being out of the usual routine (n=31/57; 54.4%) and being busy (n=22/57; 38.6%). US participants were more likely to report non-adherence due to low perceived efficacy (n=6/21, 28.6%) and cost (n=5/21, 23.8%) than German (n=1/18, 5.6%; n=0/18, 0.0%) or Spanish (n=2/18, 11.1%; n=1/18, 5.6%) participants. Conclusion: Findings highlight the diverse forms and drivers of medication non-adherence, informing the development of a comprehensive conceptual model of medication adherence. The conceptual model builds on and advances previous models of medication adherence and can be used by healthcare professionals to understand and interpret barriers to medication adherence and how best to support patients in taking their medication as intended.

Medication adherence is the extent to which a patient takes their medication as prescribed. This paper describes a literature review and concept elicitation interviews to identify forms and drivers of medication adherence across a diverse sample of participants. Forms of non-adherence identified included: deviating from the prescription, skipping a dose, taking a different amount, and taking medication at a different time. Behaviours and drivers can vary by condition, treatment modality, and dosing schedule.This research highlights the variation in the prevalence of medication non-adherence, and the different forms and drivers of non-adherence, based on individuals' demographic and clinical characteristics. The conceptual model developed advances previous models of medication adherence and may support healthcare professionals in the management of patients and how they can be supported to take medication as intended. The research ultimately informed the development of the Adelphi Adherence Questionnaire (ADAQ^©), a novel generic patient-reported outcome measure.

Factors Involved in Anti-VEGF Treatment Decisions for Neovascular Age-Related Macular Degeneration: Insights from Real-World Clinical Practice.

Background: Anti-vascular endothelial growth factor (anti-VEGF) agents are widely prescribed for the treatment of neovascular age-related macular degeneration (nAMD). Although studies have investigated patient choice of anti-VEGF agent, little is known regarding factors that influence physician preference of anti-VEGF agent for their patients. Objective: To describe physician rationale and challenges in prescribing anti-VEGF treatments for patients with nAMD. Methods: Data were drawn from the Adelphi Real World nAMD Disease Specific Programme™, a cross-sectional survey with retrospective data capture of physicians and their patients with nAMD in the United States between October 2021 and May 2022. Physicians (n = 56) reported data for up to 13 consecutively consulting patients (n = 451), including current anti-VEGF treatments used, factors affecting physicians' choice of anti-VEGF agent and treatment strategy, and restrictions on specific agents. Results: Most physicians prefer employing a "treat-and-extend" treatment strategy, over "fixed interval" or "pro re nata" strategies. However, in routine clinical practice, "treat-and-extend" was reported for less than half of nAMD-diagnosed eyes. Top factors influencing physician choice of anti-VEGF agent and treatment strategy included maximizing clinical benefit (eg visual acuity gains and fluid control), patient convenience, and reducing out-of-pocket costs. However, physicians also reported facing substantial roadblocks in prescribing their choice of anti-VEGF agent, including restrictions on approved agents and gaps in insurance coverage. Persistent fluid was the most common physician-selected reason for switching a patient away from an anti-VEGF agent. Conclusion: Physicians face barriers to prescribing their preferred anti-VEGF agents in real-world healthcare settings. Overcoming these challenges may improve treatment outcomes for patients with nAMD.

People with wet age-related macular degeneration (wet AMD) have problems with their eyesight that can lead to blindness if left untreated. Eye doctors (ophthalmologists) use a class of medicine called anti-VEGF agents to treat people with wet AMD. However, eye doctors often face challenges in prescribing their anti-VEGF agent of choice. We surveyed eye doctors to determine the reasons why they preferred some anti-VEGF agents over others, as well as the barriers to prescribing these anti-VEGF agents. Eye doctors reported that they usually choose a specific anti-VEGF agent because it leads to better vision, has lower cost for people with wet AMD, or may reduce the number of appointments needed for people with wet AMD. Eye doctors also noted that they face challenges in treating people with wet AMD, including restrictions and limited insurance coverage for certain anti-VEGF agents. Solving these problems could help eye doctors use their medicine of choice and improve eyesight even more when they treat people with wet AMD.

Canadian Society of Clinical Chemists Harmonized Pediatric Lipid Reporting Recommendations for Clinical Laboratories.

Detecting dyslipidemia early is important because atherosclerosis originates in childhood and early treatment can improve outcomes. In 2022, the Canadian Cardiovascular Society (CCS) and Canadian Pediatric Cardiology Association (CPCA) published a clinical practice update to detect, evaluate, and manage pediatric dyslipidemia. However, guidance on its translation into clinical laboratories is lacking. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team aims to assist guideline implementation and promote harmonized pediatric lipid reporting across Canada. The 2022 CCS/CPCA clinical practice update, 2011 National Heart, Lung, and Blood Institute integrated guidelines, and new data analysis (Canadian pediatric reference values from the Canadian Laboratory Initiative on Pediatric Reference Intervals [CALIPER] and retrospective patient data from large community laboratories) were incorporated to develop 5 key recommendations. These include recommendations to: (1) offer nonfasting and fasting lipid testing; (2) offer a lipid panel including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides, with apolipoprotein B and lipoprotein(a) available as individually orderable tests; (3) flag total cholesterol, LDL-C, and non-HDL-C results ≥ 95th percentile, and HDL-C results < 10th percentile, as recommended by CCS/CPCA/National Heart, Lung, and Blood Institute and validated by CALIPER, and flag apolipoprotein B and nonfasting triglyceride results ≥ 95th percentile on the basis of CALIPER, and do not flag Lp(a) results but mention the adult cutoff in the interpretive comments; (4) implement interpretive comments listed in the current report; and (5) implement the National Institutes of Health LDL-C equation. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team will support clinical laboratories to implement these recommendations using knowledge translation strategies. Harmonizing pediatric lipid reporting across Canadian clinical laboratories will optimize clinical decision-making and improve cardiovascular risk management in youth.

Pediatric reference intervals for serum neurofilament light and glial fibrillary acidic protein using the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort.

OBJECTIVES: Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. Normative data are important in children as little is known about how brain development may impact potential biomarkers. The objective of this study is to generate pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker. METHODS: Serum from healthy children and adolescents aged 1 to <19 years were obtained from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. Serum NfL (n=300) and GFAP (n=316) were quantified using Simoa technology, and discrete RI (2.5th and 97.5th percentiles) and continuous RI (5th and 95th percentiles) were generated. RESULTS: While there was no association with sex, there was a statistically significant (p<0.0001) negative association between age and serum NfL (Rho -0.400) and GFAP (Rho -0.749). Two statistically significant age partitions were generated for NfL: age 1 to <10 years (lower, upper limit; 3.13, 20.6 pg/mL) and 10 to <19 years (1.82, 7.44 pg/mL). For GFAP, three statistically significant age partitions were generated: age 1 to <3.5 years (80.4, 601 pg/mL); 3.5 to <11 years (50.7, 224 pg/mL); and 11 to <19 years (26.2, 119 pg/mL). CONCLUSIONS: Taken together with the literature on adults, NfL and GFAP display U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.

Advances in preeclampsia testing.

Preeclampsia is a multisystem hypertensive disorder and one of the leading causes of maternal and fetal morbidity and mortality. The clinical hallmarks such as hypertension and proteinuria, and additional laboratory tests currently available including liver enzyme testing, are neither specific nor sufficiently sensitive. Therefore, biomarkers for timely and accurate identification of patients at risk of developing preeclampsia are extremely valuable to improve patient outcomes and safety. In this chapter, we will first discuss the clinical characteristics of preeclampsia and current evidence of the role of angiogenic factors, such as placental growth factor (PlGF) and soluble FMS like tyrosine kinase 1 (sFlt-1) in the pathogenesis of preeclampsia. Second, we will review the clinical practice guidelines for preeclampsia diagnostic criteria and their recommendations on laboratory testing. Third, we will review the currently available PlGF and sFlt-1 assays in terms of their methodologies, analytical performance, and clinical diagnostic values. Finally, we will discuss the future research needs from both an analytical and clinical perspective.

Mining the Gap: Deriving Pregnancy Reference Intervals for Hematology Parameters Using Clinical Datasets.

BACKGROUND: Physiological changes during pregnancy invalidate use of general population reference intervals (RIs) for pregnant people. The complete blood count (CBC) is commonly ordered during pregnancy, but few studies have established pregnancy RIs suitable for contemporary Canadian mothers. Prospective RI studies are challenging to perform during pregnancy while retrospective techniques fall short as pregnancy and health status are not readily available in the laboratory information system (LIS). This study derived pregnancy RIs retrospectively using LIS data linked to provincial perinatal registry data. METHODS: A 5-year healthy pregnancy cohort was defined from the British Columbia Perinatal Data Registry and linked to laboratory data from two laboratories. CBC and differential RIs were calculated using direct and indirect approaches. Impacts of maternal and pregnancy characteristics, such as age, body mass index, and ethnicity, on laboratory values were also assessed. RESULTS: The cohort contained 143 106 unique term singleton pregnancies, linked to >972 000 CBC results. RIs were calculated by trimester and gestational week. Result trends throughout gestation aligned with previous reports in the literature, although differences in exact RI limits were seen for many tests. Trimester-specific bins may not be appropriate for several CBC parameters that change rapidly within trimesters, including red blood cells (RBCs), some leukocyte parameters, and platelet counts. CONCLUSIONS: Combining information from comprehensive clinical databases with LIS data provides a robust and reliable means for deriving pregnancy RIs. The present analysis also illustrates limitations of using conventional trimester bins during pregnancy, supporting use of gestational age or empirically derived bins for defining CBC normal values during pregnancy.

Real-world evidence generation from patients, their caregivers and physicians supporting clinical, regulatory and guideline decisions: an update on Disease Specific Programmes.

OBJECTIVE: To update on and describe the role of Disease Specific Programmes (DSPs), a multi-perspective real-world data (RWD) source, in the context of the evolution of the value and acceptance of real-world evidence (RWE) in clinical, regulatory and guideline decision-making. METHODS: DSPs are multi-national, multi-subscriber, multi-therapy cross-sectional surveys incorporating retrospective data collection from patient, caregiver and physician perspectives. Information collected covers the patient journey, including treatment/prescribing patterns and rationale, patient-reported outcomes, impact on work and everyday activities, attitudes towards and perceptions of the condition, adherence to treatment and burden of illness. Published peer-reviewed DSP papers were aligned with current key RWE themes identified in the literature, alongside their contribution to RWE. RESULTS: RWE themes examined were: using RWE to inform clinical practice, patient and caregiver engagement, RWE role in supporting health technology assessments and regulatory submissions, informing value-driven healthcare decisions, real-world patient subgroup differences and therapeutic inertia/unmet needs; highlighting patients' and caregivers' experience of living with a disease, disconnect from their physicians, unmet needs and educational gaps. CONCLUSIONS: DSPs provide a wealth of RWD in addition to evidence generated by registries, clinical trials and observational research, with wide use for the pharmaceutical industry, government, funding/regulatory bodies, clinical practice guideline insights and, most importantly, informing improvements in people's lives. The depth, breadth and heritage of information collected via DSPs since 1995 is unparalleled, extending understanding of how diseases are managed by physicians in routine clinical practice and why treatment choices are made, patients' perceptions of their disease management, and caregiver burden.

Cross-walk of the Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis (CLDQ-NASH) and the EuroQol EQ-5D-5L in patients with NASH.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic progression of nonalcoholic fatty liver disease, which can negatively impact the health-related quality of life (HRQoL) of affected individuals. HRQoL in NASH has been assessed using the disease-specific Chronic Liver Disease Questionnaire for NASH (CLDQ-NASH) and the generic EuroQol EQ-5D-5L. As the performance of these instruments relative to each other is unknown, we performed a cross-walk analysis of CLDQ-NASH to EQ-5D-5L using data from a real-world NASH population. METHODS: Data were drawn from the Adelphi Real World 2019 NASH Disease Specific Programme, a cross-sectional survey of physicians and their patients in the United States. Patients with physician-diagnosed NASH completed a questionnaire that included the CLDQ-NASH and EQ-5D-5L. Mapping from CLDQ-NASH to EQ-5D-5L was done using tenfold cross-validation; performance was assessed using root-mean squared error as accuracy measure. Subgroup analyses compared performance of the models in obese versus non-obese patients and patients with versus without type 2 diabetes (T2D). RESULTS: Data from 347 patients were included in this analysis. Overall, 2172 models were tested for predicting EQ-5D-5L index score from CLDQ-NASH score. The best model for this mapping was a generalized linear model using Gaussian distribution and a power link. The best model for mapping from CLDQ-NASH domains to the EQ-5D-5L was a fractional logistic model. Models performed better at predicting upper versus lower values of EQ-5D-5L, for non-obese versus obese patients, and for patients without versus with T2D. CONCLUSION: We describe a scoring algorithm for cross-walking the CLDQ-NASH to the EQ-5D-5L enabling health status comparisons of HRQoL across studies.

Reference Values for Videofluoroscopic Measures of Swallowing: An Update.

PURPOSE: It is essential that clinicians have evidence-based benchmarks to support accurate diagnosis and clinical decision making. Recent studies report poor reliability for diagnostic judgments and identifying mechanisms of impairment from videofluoroscopy (VFSS). Establishing VFSS reference values for healthy swallowing would help resolve such discrepancies. Steele et al. (2019) released preliminary reference data for quantitative VFSS measures in healthy adults aged < 60 years. Here, we extend that work to provide reference percentiles for VFSS measures across a larger age span. METHOD: Data for 16 VFSS parameters were collected from 78 healthy adults aged 21-82 years (39 male). Participants swallowed three comfortable sips each of thin, slightly, mildly, moderately, and extremely thick barium (20% w/v). VFSS recordings were analyzed in duplicate by trained raters, blind to participant and task, using the Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) Method. Reference percentiles (p2.5, 5, 25, 50, 75, 95, and 97.5) were determined as per Clinical and Laboratory Standards Institute EP28-A3c guidelines. RESULTS: We present VFSS reference percentile tables, by consistency, for (a) timing parameters (swallow reaction time; the hyoid burst-to-upper esophageal sphincter (UES)-opening interval; UES opening duration; time-to-laryngeal vestibule closure (LVC); and LVC duration) and (b) anatomically scaled pixel-based measures of maximum UES diameter, pharyngeal area at maximum pharyngeal constriction and rest, residue (vallecular, pyriform, other pharyngeal locations, total), and hyoid kinematics (X, Y, XY coordinates of peak position; speed). Clinical decision limits are proposed to demarcate atypical values of potential clinical concern. CONCLUSION: These updated reference percentiles and proposed clinical decision limits are intended to support interpretation and reliability for VFSS assessment data. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24043041.

Reference Interval Harmonization: Harnessing the Power of Big Data Analytics to Derive Common Reference Intervals across Populations and Testing Platforms.

BACKGROUND: Harmonization in laboratory medicine is essential for consistent and accurate clinical decision-making. There is significant and unwarranted variation in reference intervals (RIs) used by laboratories for assays with established analytical traceability. The Canadian Society of Clinical Chemists (CSCC) Working Group on Reference Interval Harmonization (hRI-WG) aims to establish harmonized RIs (hRIs) for laboratory tests and support implementation. METHODS: Harnessing the power of big data, laboratory results were collected across populations and testing platforms to derive common adult RIs for 16 biochemical markers. A novel comprehensive approach was established, including: (a) analysis of big data from community laboratories across Canada; (b) statistical evaluation of age, sex, and analytical differences; (c) derivation of hRIs using the refineR method; and (d) verification of proposed hRIs across 9 laboratories with different instrumentation using serum and plasma samples collected from healthy Canadian adults. RESULTS: Harmonized RIs were calculated for all assays using the refineR method, except free thyroxine. Derived hRIs met proposed verification criterion across 9 laboratories and 5 manufacturers for alkaline phosphatase, albumin (bromocresol green), chloride, lactate dehydrogenase, magnesium, phosphate, potassium (serum), and total protein (serum). Further investigation is needed for some analytes due to failure to meet verification criteria in one or more laboratories (albumin [bromocresol purple], calcium, total carbon dioxide, total bilirubin, and sodium) or concern regarding excessively wide hRIs (alanine aminotransferase, creatinine, and thyroid stimulating hormone). CONCLUSIONS: We report a novel data-driven approach for RI harmonization. Findings support feasibility of RI harmonization for several analytes; however, some presented challenges, highlighting limitations that need to be considered in harmonization and big data analytics.

Analytical Unreliability of 25 Hydroxy Vitamin D Measurements in Pre-Term Neonates.

BACKGROUND: Vitamin D supplementation is common practice for neonates and infants due to limited stores of vitamin D at birth. Although not commonly encountered, vitamin D toxicity can occur due to over-supplementation. However, toxic concentrations are often not included in method validation experiments, and assays often are not validated in the neonatal population. METHODS: We compared serial 25 hydroxy vitamin D [25(OH)D] measurements in pre-term neonates receiving 25(OH)D supplementation and identified 12 patients wherein concentrations of 25(OH)D were above 50 ng/mL (125 nM) that required additional investigations as the 25(OH)D results did not match the clinical picture. Available samples were compared across 4 immunoassay platforms (LIAISON XL, Roche Cobas e602, Abbott Alinity i, and Siemens Centaur XP) and LC-MS/MS. RESULTS: Concentrations of 25(OH)D observed on one individual immunoassay platform (LIAISON XL) fluctuated substantially between subsequent blood draws in select neonates with elevated concentrations. Serum samples from these patients showed variable agreement between LC-MS/MS and other immunoassay platforms. These fluctuations were not explained by the presence of 3-epimer-25(OH)D or 24,25(OH)2D. CONCLUSIONS: Although we were unable to identify a cause for the variable elevated results, our findings suggest that neonatal 25(OH)D measurements alone should not be used for assessment of nutritional monitoring, and that clinical correlation and other laboratory parameters including ionized calcium should be considered.

Highly sensitive tandem mass spectrometric measurement of serum estradiol without derivatization and pediatric reference intervals in children and adolescents.

OBJECTIVES: Monitoring estradiol (E2) is important for determining the onset of pubertal development as well as in the evaluation of girls with precocious puberty. However, E2 measurement remains an analytical challenge in children, who have lower circulating levels. We developed and evaluated a simple and sensitive LC-MS/MS procedure for serum E2 quantification in pediatric populations and established age- and sex-specific pediatric reference intervals. METHODS: Residual patient serum samples were used to evaluate the analytical performance of our in-house LC-MS/MS E2 assay. The evaluation included accuracy, precision, linearity, functional sensitivity (LLoQ), and method comparison. Age- and sex-specific pediatric E2 reference intervals were also established from a cohort of 405 healthy children (birth to 18 years) recruited with informed consent. Age- and sex-specific differences were assessed, and outliers were removed. Reference intervals were established using the robust method. RESULTS: The assay imprecision was <5.3 %. Assay linearity ranged from 13.7 to 1923.3 pmol/L. The LLoQ corresponding to a CV of 20 % was determined to be 8.9 pmol/L. Bland-Altman analysis revealed a mean bias of 29.3 pmol/L or 9.1 % between our LC-MS/MS E2 assay and an external reference laboratory measuring E2 by LC-MS/MS. CONCLUSIONS: Our LC-MS/MS E2 assay shows acceptable accuracy, precision, functional sensitivity (LLoQ), and linearity for E2 quantification. Our LC-MS/MS E2 assay also showed good agreement with an external reference laboratory measuring E2 by LC-MS/MS. In addition, using CALIPER samples, we established robust age- and sex-specific pediatric E2 reference intervals to improve accuracy of test result interpretation and clinical decision making.

Alignment of Physician-Stated vs Clinically Derived Reference Fibrosis Score in Patients with Non-Alcoholic Steatohepatitis: A Real-World European Survey.

Objective: Stratifying disease severity in patients with non-alcoholic steatohepatitis (NASH) is essential for appropriate treatment and long-term management. Liver biopsy is the reference standard for fibrosis severity in NASH, but less invasive methods are used, eg, Fibrosis-4 Index (FIB-4) and vibration-controlled transient elastography (VCTE), for which reference thresholds for no/early fibrosis and advanced fibrosis are available. We compared subjective physician assessment of NASH fibrosis versus reference thresholds to understand classification in a real-world setting. Methods: Data were drawn from Adelphi Real World NASH Disease Specific ProgrammeTM conducted in France, Germany, Italy, Spain and UK in 2018. Physicians (diabetologists, gastroenterologists, hepatologists) completed questionnaires for five consecutive NASH patients presenting for routine care. Physician-stated fibrosis score (PSFS) based on available information was compared with clinically defined reference fibrosis stage (CRFS) determined retrospectively using VCTE and FIB-4 data and eight reference thresholds. Results: One thousand two hundred and eleven patients had VCTE (n = 1115) and/or FIB-4 (n = 524). Depending on thresholds, physicians underestimated severity in 16-33% (FIB-4) and 27-50% of patients (VCTE). Using VCTE ≥12.2, diabetologists, gastroenterologists and hepatologists underestimated disease severity in 35%, 32%, and 27% of patients, respectively, and overestimated fibrosis in 3%, 4%, and 9%, respectively (p = 0.0083 across specialties). Hepatologists and gastroenterologists had higher liver biopsy rates than diabetologists (52%, 56%, 47%, respectively). Conclusion: PSFS did not consistently align with CRFS in this NASH real-world setting. Underestimation was more common than overestimation, potentially leading to undertreatment of patients with advanced fibrosis. More guidance on interpreting test results when classifying fibrosis is needed, thereby improving management of NASH.

Clinical Validation of the sFlt-1:PlGF Ratio as a Biomarker for Preeclampsia Diagnosis in a High-Risk Obstetrics Unit.

BACKGROUND: Preeclampsia is a multisystem disorder defined by new onset of hypertension with proteinuria after 20 weeks gestation. In part due to dysregulation of pro-angiogenic factors (e.g., placental growth factor [PlGF]) and anti-angiogenic factors (e.g., soluble fms-like tyrosine kinase 1 [sFlt-1]), preeclampsia results in decreased placental perfusion. An increased sFlt-1:PlGF ratio is associated with increased risk of preeclampsia. In this study, we evaluated sFlt-1:PlGF cutoffs and evaluated the clinical performance of sFlt-1:PlGF for predicting preeclampsia. METHODS: sFlt-1:PlGF results from 130 pregnant females with clinical suspicion of preeclampsia were used to evaluate the diagnostic accuracy of different sFlt-1:PlGF cutoffs and to compare the clinical performance of sFlt-1:PlGF to traditional preeclampsia markers (proteinuria and hypertension). Serum sFlt-1 and PlGF were measured using Elecsys immunoassays (Roche Diagnostics) and preeclampsia diagnosis was verified by expert chart review. RESULTS: A sFlt-1:PlGF cutoff of >38 yielded the greatest diagnostic accuracy of 90.8% (95% CI, 85.8%-95.7%). Using a cutoff of >38, sFlt-1:PlGF exhibited a greater diagnostic accuracy than traditionally used parameters such as new or worsening proteinuria or hypertension (71.9% and 68.6%, respectively). sFlt-1:PlGF >38 exhibited a negative predictive value (NPV) of 96.4% for rule-out of preeclampsia within 7 days, and a positive predictive value (PPV) of 84.8% for predicting preeclampsia within 28 days. CONCLUSIONS: Our study shows the superior clinical performance of sFlt-1:PlGF over hypertension and proteinuria alone to predict preeclampsia at a high-risk obstetrical unit.

The Present and Future of Lipid Testing in Cardiovascular Risk Assessment.

BACKGROUND: Lipids play a central role in the pathogenesis of cardiovascular disease (CVD), a leading cause of morbidity and mortality worldwide. Plasma lipids and lipoproteins are routinely measured to help identify individuals at high risk of developing CVD and to monitor patients' response to therapy. The landscape of lipid testing is rapidly changing, including new ways to estimate traditional lipid parameters (e.g., low-density lipoprotein-cholesterol [LDL-C] calculations) and new lipid parameters that show superiority for risk prediction (e.g., non-high-density lipoprotein-cholesterol [non-HDL-C], apolipoprotein B [apoB], and lipoprotein a [Lp(a)]). CONTENT: Various national guidelines for managing dyslipidemia to prevent CVD are available, which primarily focus on LDL-C for identifying those at high risk and setting thresholds for optimal response to therapy. However, LDL-C can be calculated and measured in various ways, each with advantages and disadvantages. Importantly, the recently established Sampson-NIH LDL-C equation appears to be superior to preceding calculations, as is clear from the literature and in guidelines. There is now a shift towards using lipid parameters other than LDL-C, such as non-HDL-C, apoB, and Lp(a), to identify high-risk patients and/or establish treatment targets. SUMMARY: The goal of this review is to discuss the present and future of lipid testing for CVD risk assessment through describing various national clinical guidelines, critically reviewing methods to calculate and measure LDL-C and discussing the clinical utility of additional lipid parameters.

Evaluation of hemolysis, lipemia, and icterus interference with common clinical immunoassays.

OBJECTIVES: Hemolysis, icterus, and lipemia (HIL) are common sources of endogenous interference in clinical laboratory testing. Defining the threshold of interference for immunoassays enables appropriate reporting of their results when they are affected by HIL. METHODS: Pools of residual patient serum samples were spiked with a known amount of interferent to create samples with varying concentrations of hemolysate, bilirubin, and Intralipid that mimicked the effects of endogenous HIL. Samples were analysed on the Alinity i analyser (Abbott Diagnostics) for more than 25 immunoassays. The average recovery relative to the non-spiked sample was calculated for each interference level and was compared to a predefined allowable bias. RESULTS: C-peptide, estradiol, serum folate, free T4, homocysteine, insulin, and vitamin B12 were found to be affected by hemolysis, at hemoglobin concentrations between 0.3 to 20 g/L. Immunoassays for BNP, estradiol, free T3, and homocysteine were affected by icterus at conjugated bilirubin concentrations between 50 to 1,044 µmol/L. BNP, serum folate, and homocysteine were affected by Intralipid with measured triglyceride concentrations between 0.8 to 10 mmol/L. Lastly, serological immunoassays for HIV and hepatitis A, B and C were also affected by interferences. CONCLUSIONS: Immunoassays are impacted by varying degrees of HIL interference. Some measurands, in the presence of interference, are affected in a manner not previously indicated. The data presented herein provide an independent evaluation of HIL thresholds and will be of aid to resource-limited clinical laboratories that are unable to internally verify endogenous interferences when implementing the Alinity i analyser.

Qualitative Interviews to Support Development and Cognitive Debriefing of the Adelphi Adherence Questionnaire (ADAQ©): A Patient-Reported Measure of Medication Adherence Developed for Use in a Range of Diseases, Treatment Modalities, and Countries.

Purpose: The Adelphi Adherence Questionnaire (ADAQ©) is a newly developed generic patient-reported outcome (PRO) assessment of medication adherence. The aim was to assess its content validity by conducting cognitive debriefing (CD) interviews with patients prescribed medication(s) of various treatment modalities in a range of therapy areas. Materials and Methods: Targeted literature/instrument review and concept elicitation interviews informed development of the ADAQ©. CD interviews were conducted with 57 adults from the United States of America (USA; n = 21), Spain (n = 18), and Germany (n = 18) who prescribed medication for hypertension, diabetes, depression, schizophrenia, asthma, multiple myeloma, psoriasis, and/or multiple sclerosis. Interviews were conducted in two rounds to explore the relevance and understanding of the item wording, instructions, recall period and response options. Verbatim transcripts were analysed in ATLAS.Ti using thematic analysis. Three expert clinicians provided guidance throughout the study. Results: ADAQ© items/instructions were well understood and relevant to participants. Key modifications following round 1 included revising instructions to refer to current medication(s) for one condition to reduce cognitive burden, removing two items with lower relevance (specifically those assessing running out of medication and social discouragement), and adding a response option for participants to indicate if they had stopped taking a medication. Minor wording modifications were made following round 2. Subgroup differences in item relevance were explored based on clinical characteristics. Cost of medication was more relevant amongst US participants. Conclusion: Content validity of the ADAQ© was confirmed in demographically and clinically diverse participants. Psychometric properties of the ADAQ© will be explored in future studies.

Canadian Society of Clinical Chemists Harmonized Clinical Laboratory Lipid Reporting Recommendations on the Basis of the 2021 Canadian Cardiovascular Society Lipid Guidelines.

There is limited guidance on laboratory reporting and interpretation of lipids and lipoproteins used in cardiovascular risk stratification. This contributes to inconsistencies in lipid reporting across clinical laboratories. Recently, the Canadian Cardiovascular Society (CCS) published the 2021 CCS guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. A subcommittee of the Working Group on Reference Interval Harmonization of the Canadian Society of Clinical Chemists has developed harmonized lipid reporting recommendations that are aligned with the 2021 CCS guidelines, to improve the standardization of lipid assessment and clinical decision-making. The proposed harmonized lipid reporting recommendations were critically reviewed by a broad range of laboratory and clinical experts across Canada. Feedback from approximately 30 expert reviewers was reviewed by the Working Group on Reference Interval Harmonization lipid subcommittee, and consensus decisions were incorporated into the 2021 harmonized lipid reporting recommendations. In this position statement, we provide 6 recommendations for laboratory reporting of lipid parameters. These recommendations include implementing the new National Institutes of Health equation to replace the Friedewald equation for calculating low-density lipoprotein cholesterol, offering lipoprotein (a), either as an in-house or send-out test, and using assays that report lipoprotein (a) in molar units (nmol/L). We also developed a harmonized lipid reporting format with interpretive comments that includes flagging results based on screening patients using treatment decision thresholds in a primary prevention setting. Overall, harmonized lipid reporting will help bridge the gap between clinical guideline recommendations and clinical laboratory reporting and interpretation, and will improve cardiovascular risk assessment across Canada.