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.

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.

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis (NASH) in the United Kingdom (UK) in 2018.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) - a progressive subset of non-alcoholic fatty liver disease (NAFLD) - is a chronic liver disease that can progress to advanced fibrosis, cirrhosis, and end-stage liver disease (ESLD) if left untreated. Early-stage NASH is usually asymptomatic, meaning a large proportion of the prevalent population are undiagnosed. Receiving a NASH diagnosis increases the probability that a patient will receive interventions for the purpose of managing their condition. The purpose of this study was to estimate the disease burden and economic impact of diagnosed NASH in the United Kingdom (UK) adult population in 2018. METHODS: The socioeconomic burden of diagnosed NASH from a societal perspective was estimated using cost-of-illness methodology applying a prevalence approach. This involved estimating the number of adults with diagnosed NASH in the UK in a base period (2018) and the economic and wellbeing costs attributable to diagnosed NASH in that period. The analysis was based on a targeted review of the scientific literature, existing databases and consultation with clinical experts, health economists and patient groups. RESULTS: Of the prevalent NASH population in the UK in 2018, an estimated 79.8% were not diagnosed. In particular, of the prevalent population in disease stages F0 to F2, only 2.0% (F0), 2.0% (F1) and 16.5% (F2), respectively, were diagnosed. Total economic costs of diagnosed NASH in the UK ranged from £2.3 billion (lower prevalence scenario, base probability of diagnosis scenario) to £4.2 billion (higher prevalence scenario, base probability of diagnosis scenario). In 2018, people with NASH in the UK were estimated to experience 94,094 to 174,564 disability-adjusted life years (DALYs) overall. Total wellbeing costs associated with NASH in 2018 were estimated to range between £5.6 to £10.5 billion. CONCLUSION: The prevention and appropriate management of adult NASH patients could result in reduced economic costs and improvements in wellbeing.

A Snapshot of Lipid-Reporting Practices in Canadian Clinical Laboratories: An Urgent Need for Harmonisation.

To effectively implement the Canadian Cardiovascular Society (CCS) guidelines for dyslipidemia management into clinical laboratories, clear recommendations for lipid reporting are essential. In this study, the Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonisation surveyed Canadian laboratories on adult lipid reporting practices to set a foundation for the development and implementation of harmonised lipid reporting across Canada. Key aspects of the survey asked laboratories: what reporting parameters were in place to assess lipid results; what interpretative comments were provided; whether nonfasting lipids were permitted and, if so, what strategy was used to document fasting status; and whether there was interest in implementing a harmonised lipid report. A total of 101 laboratories were represented by 24 respondents, as many responses were submitted by laboratory networks that included more than 1 laboratory. There was at least 1 response from 9 Canadian provinces and representation across 5 testing platforms. Upper and lower limits for lipid parameters and referenced source of limits varied substantially across laboratories, with only 56% of laboratories (9 respondents) referencing the 2016 CCS guidelines. Eighty-six percent of laboratories (19 respondents) report nonfasting lipids, although the method of documenting nonfasting status varied. Overall, 36% of laboratories (8 respondents) reported interest in implementing a harmonised lipid report. Assessment of current lipid-reporting practices supports the need for harmonised lipid reporting across Canada. Development of a harmonised lipid report for the adult population, consistent with up-to-date Canadian guidelines, will improve continuity of lipid test interpretation across Canada and improve clinical decision making.

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018. METHODS: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups. RESULTS: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time. CONCLUSIONS: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs.

Postprandial Dyslipidemia: Pathophysiology and Cardiovascular Disease Risk Assessment.

Although the fed state predominates over the course of a day, the fasting lipid profile has traditionally been used to assess cardiovascular disease (CVD) risk. The nonfasting lipid profile may be more reflective of the daily circulating plasma lipids and simplifies lipid monitoring for patients, laboratories, and clinicians. Nonfasting triglyceride levels are also independently associated with cardiovascular events, leading to several clinical guidelines (e.g. in Denmark, the UK, Europe, and Canada) now recommending nonfasting lipid testing in the primary prevention setting. Obese and insulin resistant states are associated with intestinal chylomicron overproduction and subsequent remnant lipoprotein accumulation, leading to development of postprandial dyslipidemia in the fed state. Postprandial dyslipidemia is thought to be a major contributor of atherogenesis and shown to be an important CVD risk factor. As intestinal peptides (e.g. glucagon-like-peptide 1; GLP-1) have been shown to regulate chylomicron output, alterations in these signaling pathways in insulin resistant states may play a role in the development and/or progression of postprandial dyslipidemia. Although several advances have been made in understanding postprandial dyslipidemia in insulin resistance and its association with CVD, several limitations remain. Although nonfasting lipid measurements (i.e. random blood sampling) are now recommended in some countries, a more functional assessment of postprandial lipemia involves ingestion of a high-fat meal with subsequent blood collection over a specified time period (i.e. oral fat tolerance test). However, oral fat tolerance test methodology remains largely unstandardized and reference values to interpret postprandial values remain to be accurately established. Development of standardized methodologies and biomarker profiles for assessment of postprandial dyslipidemia in clinical practice will enable early and accurate identification of those at risk for CVD.

Pediatric Metabolic Syndrome: Pathophysiology and Laboratory Assessment.

Pediatric overweight and obesity is an emerging public health priority as rates have rapidly increased worldwide. Obesity is often clustered with other metabolic abnormalities including hypertension, dyslipidemia, and insulin resistance, leading to increased risk of cardiovascular disease. This cluster of risk factors, termed the metabolic syndrome, has traditionally been reported in adults. However, with the increased prevalence of pediatric obesity, the metabolic syndrome is now evident in children and adolescents. This complex cluster of risk factors is the result of the pathological interplay between several organs including adipose tissue, muscle, liver, and intestine with a common antecedent - insulin resistance. The association of the metabolic syndrome with several systemic alterations that involve numerous organs and tissues adds to the complexity and challenge of diagnosing the metabolic syndrome and identifying useful clinical indicators of the disease. The complex physiology of growing and developing children and adolescents further adds to the difficulties in standardizing laboratory assessment, diagnosis, and prognosis for the diverse pediatric population. However, establishing a consensus definition is critical to identifying and managing children and adolescents at high risk of developing the metabolic syndrome. As a result, the examination of novel metabolic syndrome biomarkers which can detect these metabolic abnormalities early with high specificity and sensitivity in the pediatric population has been of interest. Understanding this complex cluster of risk factors in the pediatric population is critical to ensure that this is not the first generation where children have a shorter life expectancy than their parents. This review will discuss the pathophysiology, consensus definitions and laboratory assessment of pediatric metabolic syndrome as well as potential novel biomarkers.

Laboratory reference intervals in the assessment of iron status in young children.

OBJECTIVES: The primary objective was to establish reference intervals for laboratory tests used to assess iron status in young children using the Clinical and Laboratory Standards Institute guidelines. A secondary objective was to compare the lower limit of the reference interval with the currently recommended cut-off value for haemoglobin and serum ferritin in children 1-3 years of age. METHODS: Blood samples were obtained from healthy children recruited during scheduled health supervision visits with their primary care physician. For our primary objective, outliers were removed; age partitions were selected and analysis of variance and pairwise comparisons were made between adjacent partitions; reference intervals and 90% CIs were calculated. For our secondary objective, we determined the proportion of children misclassified using the lower limit reference interval compared with the cut-off value. RESULTS: Samples from 2305 male and 2029 female participants (10 days to 10.6 years) were used to calculate age and sex-specific reference intervals for laboratory tests of iron status. There were statistically significant differences between adjacent age partitions for most analytes. Approximately 10% of children 1-3 years of age were misclassified (underestimated) using the lower limit of the reference intervals rather than the currently recommended cut-off values for haemoglobin and serum ferritin. IMPLICATIONS AND RELEVANCE: Clinical laboratories may consider adopting published paediatric reference intervals. Reference intervals may misclassify (underestimate) children with iron deficiency as compared with currently recommended cut-off values. Future research on decision limits derived from clinical studies of outcomes is a priority.

Real-world characterization and differentiation of the Global Initiative for Chronic Obstructive Lung Disease strategy classification.

BACKGROUND: This study aimed to characterize and differentiate the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy 2011 cut points through the modified Medical Research Council dyspnea scale (mMRC) and chronic obstructive pulmonary disease (COPD) assessment test (CAT). METHODS: Analysis of COPD patient data from the 2012 Adelphi Respiratory Disease Specific Program was conducted in Europe and US. Matched data from physicians and patients included CAT and mMRC scores. Receiver operating characteristic curves and kappa analysis determined a cut point for CAT and mMRC alignment and thus defined patient movement ("movers") within GOLD groups A-D, depending on the tool used. Logistic regression analysis, with a number of physician- and patient-reported covariates, characterized those movers. RESULTS: Comparing GOLD-defined high-symptom patients using mMRC and CAT cut points (≥2 and ≥10, respectively), there were 890 (53.65%) movers; 887 of them (99.66%) moved from less symptomatic GOLD groups A and C (using mMRC) to more symptomatic groups B and D (using CAT). For receiver operating characteristic (area under the curve: 0.82, P<0.001) and kappa (maximized: 0.45) recommended CAT cut points of ≥24 and ≥26, movers reduced to 429 and 403 patients, respectively. Logistic regression analysis showed variables significantly associated with movers were related to impact on normal life, age, cough, and sleep (all P<0.05). Within movers, direction of movement was significantly associated with the same variables (all P<0.05). CONCLUSION: Use of current mMRC or CAT cut points leads to inconsistencies for COPD assessment classification. It is recommended that cut points are aligned and both tools administered simultaneously for optimal patient care and to allow for closer management of movers. Our research may suggest an opportunity to investigate a combined score approach to patient management based on the worst result of mMRC and CAT. The reduced number of remaining movers may then identify patients who have greater impact of disease and may require a more personalized treatment plan.

Impact of night-time symptoms in COPD: a real-world study in five European countries.

BACKGROUND: Sleep quality is often poor in patients with chronic obstructive pulmonary disease (COPD). A cross-sectional European survey investigated the prevalence of night-time symptoms in COPD to evaluate the level of disconnect between physician and patient perceptions of the presence of night-time symptoms, and to compare the characteristics of patients with and without night-time symptoms. METHODS: A total of 251 primary care physicians and 251 respiratory specialists completed record forms on 2,807 patients with COPD. The forms captured information on patient demographics, lung function, COPD severity, and symptoms. Patients completed questionnaires on the time of day when their COPD symptoms bothered them, and the impact of COPD on their ability to get up in the morning and on sleep. Data were compared between groups (those with and without night-time symptoms) using t-tests or Wilcoxon signed rank tests. The kappa statistic was used to assess the level of disconnect between physician and patient perceptions of the impact of night-time symptoms. RESULTS: Most patients (78%) reported night-time disturbance. Patients with night-time symptoms experienced more daytime breathlessness (mean modified Medical Research Council dyspnea scale score 2.4 versus 1.1) and exacerbations in the previous 12 months (mean 1.7 versus 0.4), and received more maintenance therapy (mean of 2.8 versus 2.3 products) than those without. Concordance between the frequency of physician-reported (67.9% of patients) and patient-reported (68.5% of patients) night-time symptoms was good. Physicians significantly underestimated the impact of COPD on the patient's ability to get up in the morning and on sleep (fair-moderate agreement). Physician-reported night-time symptoms were present for 41.2% of patients who could be categorized by Global initiative for chronic Obstructive Lung Disease (GOLD) group (n=937), increasing from 20.9% of those in the low-risk group to 77.4% of those in the high-riskgroup. CONCLUSION: Patients with COPD experience night-time symptoms regardless of GOLD group, that impact on their ability to get up in the morning and on their sleep quality.

Real world COPD: association of morning symptoms with clinical and patient reported outcomes.

This research examined the prevalence of morning symptoms and their relationship with health status, exacerbations and daily activity in patients with chronic obstructive pulmonary disease (COPD). Data on 1489 patients were analysed from a European and USA sample. Results were tested for significance (p < 0.05) using Mann-Whitney and regression modelling accounting for age, gender, body mass index, comorbidities, symptom severity, smoking status and medication adherence. Morning symptoms were experienced by 39.8% of patients. Controlling for potential confounders, morning symptoms were significantly associated with higher COPD assessment test scores (p < 0.001) and exacerbation frequency (p < 0.001), more frequent worsening of symptoms without consulting a Health Care Professional (p = 0.008), and increased impact on normal daily activities (p = 0.007); and in the working population, a significantly greater impact on getting up and ready for the day (p < 0.001) and significantly more days off work per year (p < 0.001). Our research concluded that in patients with COPD, morning symptoms are associated with poorer health status, impaired daily activities and increased risk of exacerbation in affected patients compared with those patients without morning symptoms. Improved control of patients' morning symptoms may lead to substantial reduction in COPD impact and frequency of exacerbations, and enable patients to increase daily activities, particularly early morning activities. This could, in turn, enable working patients with COPD to be more productive in the workplace.