Dealing with Time in Health Economic Evaluation: Methodological Issues and Recommendations for Practice

Time is an important aspect of health economic evaluation, as the timing and duration of clinical events, healthcare interventions and their consequences all affect estimated costs and effects. These issues should be reflected in the design of health economic models. This article considers three important aspects of time in modelling: (1) which cohorts to simulate and how far into the future to extend the analysis; (2) the simulation of time, including the difference between discrete-time and continuous-time models, cycle lengths, and converting rates and probabilities; and (3) discounting future costs and effects to their present values. We provide a methodological overview of these issues and make recommendations to help inform both the conduct of cost-effectiveness analyses and the interpretation of their results. For choosing which cohorts to simulate and how many, we suggest analysts carefully assess potential reasons for variation in cost effectiveness between cohorts and the feasibility of subgroup-specific recommendations. For the simulation of time, we recommend using short cycles or continuous-time models to avoid biases and the need for half-cycle corrections, and provide advice on the correct conversion of transition probabilities in state transition models. Finally, for discounting, analysts should not only follow current guidance and report how discounting was conducted, especially in the case of differential discounting, but also seek to develop an understanding of its rationale. Our overall recommendations are that analysts explicitly state and justify their modelling choices regarding time and consider how alternative choices may impact on results

The impact of the COVID-19 pandemic on the delivery of primary percutaneous coronary intervention in STEMI

Objectives: The clinical environment has been forced to adapt to meet the unprecedented challenges posed by the COVID-19 pandemic. Intensive care facilities were expanded in anticipation of the pandemic where the consequences include severe delays in elective procedures. Emergent procedures such as Percutaneous Coronary Intervention (PCI) in acute myocardial infarction (AMI) in which delays in timely delivery have well established adverse prognostic effects must also be explored in the context of changes in procedure and public behaviour associated with the COVID-19 pandemic. The aim for this single centre retrospective cohort study is to determine if door-to-balloon (D2B) times in PCI for ST Elevation Myocardial Infarction (STEMI) during the United Kingdom’s first wave of the COVID-19 pandemic differed from pre-COVID-19 populations. Methods: Data was extracted from our single centre PCI database for all patients that underwent pPCI for STEMI. The reference (Pre-COVID-19) cohort was collected over the period 01-03-2019 to 31-05-2019 and the exposure group (COVID-19) over the period 01-03-2020 to 31-05-2020. Baseline patient characteristics for both populations were extracted. The primary outcome measurement was D2B times. Secondary outcome measurements included: time of symptom onset to call for help, transfer time to first hospital, transfer time from non-PCI to PCI centre, time from call-to-help to PCI centre, time to table and onset of symptoms to balloon time. Categorical and continuous variables were assessed with Chi squared and Mann-Whitney U analysis respectively. Procedural times were calculated and compared in the context of heterogeneity findings. Results: 4 baseline patient characteristics were unbalanced between populations with statistical significance (P<0.05). The pre-covid-19 cohort was more likely to have suffered out of hospital cardiac arrest (OHCA) and had left circumflex disease, whereas the 1st wave cohort were more likely to have been investigated with left ventriculography and be of Afro-Caribbean origin. No statistically significant difference in in-hospital procedural times was found with D2B, C2B, O2B times comparable between groups. Pre-hospital delays were the greatest contributors in missed target times: the 1st wave group had significantly longer delayed time of symptom onset to call for help (Control: 31 mins; IQR [82.5] vs 1st wave: 60 mins; IQR [90.0], P=0.001) and time taken from call for help to arrival at the PCI hospital (control: 72 mins; IQR [23] vs 1st wave: 80 mins; IQR [66.5], P=0.042). Conclusion: Enhanced infection prevention and control procedures considering the COVID-19 pandemic did not impede the delivery of pPCI in our single centre cohort. The public health impact of the pandemic has been demonstrated with times being significantly impacted by patient related delays. The recovery of public engagement in emergency medical services must become the focus for public health initiatives as we emerge from the height of COVID-19 disease burden in the UK.Publisher PDFPeer reviewe

Dealing with Time in Health Economic Evaluation: Methodological Issues and Recommendations for Practice

Time is an important aspect of health economic evaluation, as the timing and duration of clinical events, healthcare interventions and their consequences all affect estimated costs and effects. These issues should be reflected in the design of health economic models. This article considers three important aspects of time in modelling: (1) which cohorts to simulate and how far into the future to extend the analysis; (2) the simulation of time, including the difference between discrete-time and continuous-time models, cycle lengths, and converting rates and probabilities; and (3) discounting future costs and effects to their present values. We provide a methodological overview of these issues and make recommendations to help inform both the conduct of cost-effectiveness analyses and the interpretation of their results. For choosing which cohorts to simulate and how many, we suggest analysts carefully assess potential reasons for variation in cost effectiveness between cohorts and the feasibility of subgroup-specific recommendations. For the simulation of time, we recommend using short cycles or continuous-time models to avoid biases and the need for half-cycle corrections, and provide advice on the correct conversion of transition probabilities in state transition models. Finally, for discounting, analysts should not only follow current guidance and report how discounting was conducted, especially in the case of differential discounting, but also seek to develop an understanding of its rationale. Our overall recommendations are that analysts explicitly state and justify their modelling choices regarding time and consider how alternative choices may impact on results

Les chrétiens palestiniens : politique, droit et société, 1917-1948

En tant que Ville sainte, Jérusalem est indiscutablement le lieu le plus important du Moyen-Orient : pour les musulmans, le Haram al-Sharif est un symbole de victoire ; pour les Juifs, le mur des Lamentations est un symbole de perte ; et pour les chrétiens, le Saint-Sépulcre est un symbole de victoire qui passe par une perte. La religion et la politique se sont influencées l’une l’autre dans chacune de ces histoires saintes. Les théologies politiques demeurent pour le moins implicites dans le..

Age-related loss of CpG methylation in the tumour necrosis factor promoter

Background: Dysregulated production of TNF has been implicated in the pathogenesis and severity of inflammatory rheumatic diseases, many of which show age-related increased incidence. Ageing is also associated with changes in the immune system including higher systemic levels of pro-inflammatory cytokines. Methylation of DNA is an important regulator of gene expression and changes with age. Objective: In this study we investigated whether the DNA methylation status of the TNF promoter changed with age in peripheral blood leucocytes and macrophages. Methods and results: Using pyrosequencing assays we detected age-related demethylation of CpG motifs (-304, -245 and -239) in the TNF promoter in human peripheral blood cells from 312 healthy controls (0.8% per decade, confidence interval (CI) = 0.44-1.13%, p = 1 x 10(-5)) and primary monocyte-derived macrophages (MDM) from a separate population of 78 healthy controls (1.4% per decade, CI = 0.79-2.13%, p = 7 x 10(-5)). Methylation a TNF promoter fragment (-345-+154) resulted in 78% reduction of reporter gene activity compared with the unmethylated promoter construct. Conclusions: These data suggest a potential role of accrued changes in DNA methylation in the development of age-related inflammatory diseases, such as rheumatoid arthritis and polymyalgia rheumatica, in which TNF is a pivotal mediator. (C) 2011 Elsevier Ltd. All rights reserved

The Effect of Gestational and Lactational Age on the Human Milk Metabolome

Human milk is the ideal nutrition source for healthy infants during the first six months of life and a detailed characterisation of the composition of milk from mothers that deliver prematurely (&lt;37 weeks gestation), and of how human milk changes during lactation, would benefit our understanding of the nutritional requirements of premature infants. Individual milk samples from mothers delivering prematurely and at term were collected. The human milk metabolome, established by nuclear magnetic resonance (NMR) spectroscopy, was influenced by gestational and lactation age. Metabolite profiling identified that levels of valine, leucine, betaine, and creatinine were increased in colostrum from term mothers compared with mature milk, while those of glutamate, caprylate, and caprate were increased in mature term milk compared with colostrum. Levels of oligosaccharides, citrate, and creatinine were increased in pre-term colostrum, while those of caprylate, caprate, valine, leucine, glutamate, and pantothenate increased with time postpartum. There were differences between pre-term and full-term milk in the levels of carnitine, caprylate, caprate, pantothenate, urea, lactose, oligosaccharides, citrate, phosphocholine, choline, and formate. These findings suggest that the metabolome of pre-term milk changes within 5–7 weeks postpartum to resemble that of term milk, independent of time of gestation at pre-mature delivery

Quantification of Human Milk Phospholipids: the Effect of Gestational and Lactational Age on Phospholipid Composition

Human milk (HM) provides infants with macro- and micronutrients needed for growth and development. Milk phospholipids are important sources of bioactive components, such as long-chain polyunsaturated fatty acids (LC-PUFA) and choline, crucial for neural and visual development. Milk from mothers who have delivered prematurely (&lt;37 weeks) might not meet the nutritional requirements for optimal development and growth. Using liquid chromatography tandem-mass spectrometry, 31 phospholipid (PL) species were quantified for colostrum (&lt;5 days postpartum), transitional (&#8805;5 days and &#8804;2 weeks) and mature milk (&gt;2 weeks and &#8804;15 weeks) samples from mothers who had delivered preterm (n = 57) and term infants (n = 22), respectively. Both gestational age and age postpartum affected the PL composition of HM. Significantly higher concentrations (p &lt; 0.05) of phosphatidylcholine (PC), sphingomyelin (SM) and total PL were found in preterm milk throughout lactation, as well as significantly higher concentrations (p &lt; 0.002) of several phosphatidylethanolamine (PE), PC and SM species. Multivariate analysis revealed that PLs containing LC-PUFA contributed highly to the differences in the PL composition of preterm and term colostrum. Differences related to gestation decreased as the milk matured. Thus, gestational age may impact the PL content of colostrum, however this effect of gestation might subside in mature milk