Appraising Drugs Based on Cost-effectiveness and Severity of Disease in Norwegian Drug Coverage Decisions

Importance: Rising health care costs are a major health policy challenge globally. Norway has implemented a priority-setting system intended to balance cost-effectiveness and concerns for fair distribution, but little is known about this strategy and whether it works in practice. Objective: To present and evaluate a systematic drug appraisal method that uses the severity of disease to account for a fair distribution of health in cost-effectiveness analysis, forming the basis for price negotiations and coverage decisions. Design, Setting, and Participants: This cross-sectional study uses confidential drug price information and publicly available data from health technology assessments and logistic and linear regression analyses to evaluate drug coverage decisions for the Norwegian specialized health care sector from 2014 to 2019. Main Outcomes and Measures: Drug coverage decisions by Norwegian authorities and incremental cost-effectiveness and severity of disease measured as absolute shortfall of quality adjusted life years. Results: Between 2014 and 2019, a total of 188 drugs were appraised, of which 113 were cancer drugs. The overall coverage rate was 73% (138 of 188). The number of annual appraisals increased during the observation period. Based on 83 chosen decisions, regression analysis showed that incremental cost-effectiveness ratios (ICER) based on negotiated drug prices, adjusted for severity-differentiated cost-effectiveness thresholds, was the variable that best projected drug approvals (OR, 0.60; 95% CI, 0.42-0.86). An increase in the ICER by $10 000 was associated with a reduction in the odds for approval of 40% for drugs assessed from 2018 to 2019. Conclusions and Relevance: This cross-sectional study demonstrated how concerns for efficiency and fair distribution of health can be implemented systematically into drug appraisals and reimbursement decisions. New, expensive drugs are expected to escalate health care costs in the years to come, and it may be feasible to control costs by negotiating the prices of new drugs while appraising both their cost-effectiveness and how their health benefits are distributed.publishedVersio

Effectiveness and Safety of Low-Threshold Opioid-Agonist Treatment in Hard-To-Reach Populations with Opioid Dependence

Objectives: Opioid-use disorder is related to premature death worldwide. Opioid-agonist treatment (OAT) is an effective treatment for opioid dependence. OAT delivery platforms may influence treatment access and outcomes, especially for the most vulnerable groups. The aim of this study was to determine the effectiveness and safety of low-threshold OAT compared to the standard treatment. Methods: Patients with diagnosed opioid dependence undergoing low-threshold OAT at the Bergen delivery platform in Norway were enrolled in a cohort study in 2014–2019. A national OAT cohort was the reference group. The main outcomes were treatment retention, the use of illicit opioids, non-fatal overdose, overdose death, and all-cause mortality during the first year following treatment initiation and the full treatment period. Additionally, healthcare utilization in the periods before and during OAT was investigated. Results: Compared to the reference cohort, the low-threshold cohort (n = 128, mean age: 38 years, women: 28%) showed treatment retention rates of 95% versus 92%, illicit opioid use of 7% versus 10%, non-fatal overdose of 7% versus 6%, and death at 1.0% versus 1.3%, respectively. The incident rate ratios (IRRs) for healthcare utilization increased substantially during the OAT period compared to the period before; the IRR increased by 3.3 (95% confidence interval (CI): 2.8, 3.9) and 3.4 (95% CI: 3.1, 3.9) for all in- and outpatient healthcare, respectively. Conclusions: Low-threshold OAT was at least as effective and safe as the standard OAT in terms of treatment retention, the use of illicit opioids, non-fatal overdose, and death. Healthcare utilization increased during the OAT compared to the period before. Lowering the threshold for OAT entrance within proper delivery platforms should be broadly considered to reduce harm and improve healthcare access among patients with opioid dependence.publishedVersio

Sleep and physical activity from before conception to the end of pregnancy in healthy women: a longitudinal actigraphy study

Background Sleep and physical activity changes are common in pregnancy, but longitudinal data starting before conception are scarce. Our aim was to determine the changes of the daily total sleep time (TST) and physical activity duration (PAD) from before conception to end of pregnancies in respect of pregestational maternal factors. Methods This longitudinal observational study formed part of the CONIMPREG research project and recruited healthy women planning to become pregnant. Sleep and physical activity were recorded around-the-clock for ≥4 days via actigraphy before conception and during each trimester of pregnancy. Data were adjusted according to pregestational maternal body composition, parity and age. Results Among 123 women with eligible data, the unadjusted mean (95% confidence interval) TST increased from 415.3 min (405.5–425.2 min) before conception to 458.0 min (445.4–470.6 min) in the 1st trimester, remaining high through the 2nd and 3rd trimesters. Variation was substantial before conception (±2SD range: 307–523 min). The unadjusted mean PAD before conception was 363.7 min (±2SD range: 120–608 min), decreasing sharply to 262.1 min in the first trimester and more gradually thereafter. Vigorous and moderate activity decreased more than light activity. TST and PAD were significantly associated with age, parity, and pregestational body fat percentage; lean body mass was negatively correlated with TST. Results were generally unaffected by seasonal variations. Conclusion Marked variations were found in pregestational TST and PAD. Healthy women slept ≥30 min longer during pregnancy, while PAD decreased by ≥ 90 min in early pregnancy and continued to decrease thereafter.publishedVersio

Parent-of-origin-environment interactions in case-parent triads with or without independent controls

With case–parent triad data, one can frequently deduce parent of origin of the child's alleles. This allows a parent‐of‐origin (PoO) effect to be estimated as the ratio of relative risks associated with the alleles inherited from the mother and the father, respectively. A possible cause of PoO effects is DNA methylation, leading to genomic imprinting. Because environmental exposures may influence methylation patterns, gene–environment interaction studies should be extended to allow for interactions between PoO effects and environmental exposures (i.e., PoOxE). One should thus search for loci where the environmental exposure modifies the PoO effect. We have developed an extensive framework to analyze PoOxE effects in genome‐wide association studies (GWAS), based on complete or incomplete case–parent triads with or without independent control triads. The interaction approach is based on analyzing triads in each exposure stratum using maximum likelihood estimation in a log‐linear model. Interactions are then tested applying a Wald‐based posttest of parameters across strata. Our framework includes a complete setup for power calculations. We have implemented the models in the R software package Haplin. To illustrate our PoOxE test, we applied the new methodology to top hits from our previous GWAS, assessing whether smoking during the periconceptional period modifies PoO effects on cleft palate only.publishedVersio

Impaired cerebrovascular reactivity may predict delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Introduction: Delayed cerebral ischemia (DCI) is a major cause of disability and death after aneurysmal subarachnoid hemorrhage. The literature suggests that impaired cerebrovascular reactivity (CVR) may be a predictor for DCI; still no CVR based prediction model has been developed. Increased knowledge about possible predictors of DCI can improve patient management in high-risk patients and allow for shorter hospital stay in low-risk patients. Method: CVR was examined in 42 patients with aneurysmal subarachnoid hemorrhage and 37 patients treated for unruptured intracranial aneurysm, using acetazolamide test with transcranial Doppler monitoring of blood flow velocities. Patients were followed for development of DCI, separated into clinical deterioration and radiographic infarction. Results: For all patients, regardless of aneurysm rupture status, CVR was on average 5.5 percentage points lower on the ipsilateral side of aneurysm treatment. Patients with clinical deterioration due to DCI had lower CVR than patients without DCI, and the difference was larger on the contralateral side (33.9% vs. 49.2%). Two prediction models were constructed for clinical deterioration due to DCI. The area under the receiver operating characteristic curve was 0.82 in the model using established predictors, and 0.86 in the model that also included CVR. Conclusion: Our findings support the hypothesis that impaired CVR may be an independent predictor of clinical deterioration due to DCI, and may assist in identifying patients at risk after aneurysmal subarachnoid hemorrhage. Ipsilateral CVR reduction occurs in all patients after aneurysm treatment, regardless of DCI development, thus highlighting the need to evaluate ipsi- and contralateral CVR separately.publishedVersio

Estimating health adjusted age at death (HAAD)

Objectives: At any point in time, a person’s lifetime health is the number of healthy life years they are expected to experience during their lifetime. In this article we propose an equity-relevant health metric, Health Adjusted Age at Death (HAAD), that facilitates comparison of lifetime health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for estimating HAAD is presented, and we use this method to rank four conditions in six countries according to several criteria of “worse off” as a proof of concept. Methods: For individuals with specific conditions HAAD consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data from 2017 for all countries and for all diseases were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to have HAAD<20 (T20), the 25th and 75th percentiles of HAAD for affected individuals (Q1 and Q3, respectively), and the average HAAD (aHAAD) across all affected individuals. Results: Even in settings where aHAAD is similar for two conditions, other measures may vary. One example is AML (aHAAD = 59.3, T20 = 2.0%, Q3-Q1 = 14.8) and ALL (58.4, T20 = 4.6%, Q3-Q1 = 21.8) in the US. Many illnesses, such as epilepsy, are associated with more lifetime health in high-income settings (Q1 in Japan = 59.2) than in low-income settings (Q1 in Ethiopia = 26.3). Conclusion: Using HAAD we may estimate the distribution of lifetime health of all individuals in a population, and this distribution can be incorporated as an equity consideration in setting priorities for health interventions.publishedVersio

Wavelet Screening identifies regions highly enriched for differentially methylated loci for orofacial clefts

DNA methylation is the most widely studied epigenetic mark in humans and plays an essential role in normal biological processes as well as in disease development. More focus has recently been placed on understanding functional aspects of methylation, prompting the development of methods to investigate the relationship between heterogeneity in methylation patterns and disease risk. However, most of these methods are limited in that they use simplified models that may rely on arbitrarily chosen parameters, they can only detect differentially methylated regions (DMRs) one at a time, or they are computationally intensive. To address these shortcomings, we present a wavelet-based method called ‘Wavelet Screening’ (WS) that can perform an epigenome-wide association study (EWAS) of thousands of individuals on a single CPU in only a matter of hours. By detecting multiple DMRs located near each other, WS identifies more complex patterns that can differentiate between different methylation profiles. We performed an extensive set of simulations to demonstrate the robustness and high power of WS, before applying it to a previously published EWAS dataset of orofacial clefts (OFCs). WS identified 82 associated regions containing several known genes and loci for OFCs, while other findings are novel and warrant replication in other OFCs cohorts.publishedVersio

Health equity impact of community-initiated kangaroo mother care: a randomized controlled trial

Background: Kangaroo mother care (KMC) can substantially enhance overall survival of low birthweight babies. In a large randomized controlled trial, we recently showed that supporting mothers to provide community initiated KMC (ciKMC) can reduce mortality among infants up to 180 days of life by 25% (hazard ratio (HR) 0.75). With the current analysis, we aimed to explore if ciKMC promotion leads to increased inequity in survival. Methods: In the trial we randomized 8402 low birthweight babies to a ciKMC (4480 babies) and a control (3922 babies) arm, between 2015 and 2018 in Haryana, India. We estimated the difference in concentration indices, which measure inequality, between babies in the ciKMC and control arms for survival until 180 days of life. Further, we compared the effect of ciKMC promotion across subgroups defined by socioeconomic status, caste, maternal literacy, infant’s sex, and religion. Results: Our intervention did not increase survival inequity, as the concentration index in the ciKMC arm of the trial was 0.05 (95% CI -0.07 to 0.17) lower than in the control arm. Survival impact was higher among those belonging to the lower two wealth quintiles, those born to illiterate mothers and those belonging to religions other than Hindu. Conclusions: We found that ciKMC promotion did not increase inequity in survival associated with wealth. The beneficial impact of ciKMC tended to be larger among vulnerable groups. Supporting mothers to provide KMC at home to low birthweight babies will not increase and could indeed reduce inequities in infant survival.publishedVersio

Who gets the ventilator? A multicentre survey of intensivists' opinions of triage during the first wave of the COVID-19 pandemic

Background The COVID-19 pandemic has caused a shortage of intensive care resources. Intensivists' opinion of triage and ventilator allocation during the COVID-19 pandemic is not well described. Methods This was a survey concerning patient numbers, bed capacity, triage guidelines, and three virtual cases involving ventilator allocations. Physicians from 400 ICUs in a research network were invited to participate. Preferences were assessed with a five-point Likert scale. Additionally, age, gender, work experience, geography, and religion were recorded. Results Of 437 responders 31% were female. The mean age was 44.4 (SD 11.1) with a mean ICU experience of 13.7 (SD 10.5) years. Respondents were mostly European (88%). Sixty-six percent had triage guidelines available. Younger patients and caretakers of children were favoured for ventilator allocation although this was less clear if this involved withdrawal of the ventilator from another patient. Decisions did not differ with ICU experience, gender, religion, or guideline availability. Consultation of colleagues or an ethical committee decreased with age and male gender. Conclusion Intensivists appeared to prioritise younger patients for ventilator allocation. The tendency to consult colleagues about triage decreased with age and male gender. Many found such tasks to be not purely medical and that authorities should assume responsibility for triage during resource scarcity.publishedVersio

Changes in life expectancy and disease burden in Norway, 1990–2019: an analysis of the Global Burden of Disease Study 2019

Bill & Melinda Gates FoundationpublishedVersio