A methodological guide for implementing and interpreting results of probabilistic analysis.

Introduction: Probabilistic analysis, also referred to as probabilistic sensitivity analysis (PSA), is used extensively in cost-effectiveness evaluations of health technologies. We present methodological guidance for implementing probabilistic analysis and interpreting its results for policy and decision-making.

Methods: We review the methodological issues related to common practices in probabilistic analysis, explore aspects that are currently not widely addressed in the health economics literature, and provide an overview of recent methodological developments.

Simplified Methods for Modelling Dependent Parameters in Health Economic Evaluations: A Tutorial.

Background: In health economic evaluations, model parameters are often dependent on other model parameters. Although methods exist to simulate multivariate normal (MVN) distribution data and estimate transition probabilities in Markov models while considering competing risks, they are technically challenging for health economic modellers to implement. This tutorial introduces easily implementable applications for handling dependent parameters in modelling.

Understanding bias in probabilistic analysis in model-based health economic evaluation.

Guidelines of economic evaluations suggest that probabilistic analysis (using probability distributions as inputs) provides less biased estimates than deterministic analysis (using point estimates) owing to the non-linear relationship of model inputs and model outputs. However, other factors can also impact the magnitude of bias for model results. We evaluate bias in probabilistic analysis and deterministic analysis through three simulation studies.

Examining the correlation between treatment effects in clinical trials and economic modeling.

Introduction: Many diseases have a sequential treatment pathway. Compared with patients without previous treatment, patients who fail initial treatment may have lower success rates with a second treatment. This phenomenon can be explained by a correlation between treatment effects.

Developing Economic Models for Assessing the Cost-Effectiveness of Multiple Diagnostic Tests: Methods and Applications.

Background: Clinical pathways with multiple diagnostic tests are complex to model, but problematic and simplistic approaches are often used in economic evaluations.

Methods: We analyzed statistical methods of handling multiple diagnostic tests and provided guidance on applying these methods in economic modeling. We first introduced a statistical model to quantify the correlations between 2 tests and how those correlations can be incorporated within an economic model.

Review and estimation of disutility for joint health states of severe and nonsevere hypoglycemic events in diabetes.

Many economic evaluations used linear or log-transformed additive methods to estimate the disutility of hypoglycemic events in diabetes, both nonsevere (NSHEs) and severe (SHEs). We conducted a literature search for studies of disutility for hypoglycemia. We used additive, minimum and multiplicative methods, and the adjusted decrement estimator to estimate the disutilities of joint health states with both NSHEs and SHEs in six scenarios.

Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions in Average-Risk Pregnancies: A Cost-Effectiveness Analysis.

Objective: The cost effectiveness of noninvasive prenatal testing (NIPT) has been established for high-risk pregnancies but remains unclear for pregnancies at other risk levels. The aim was to assess the cost effectiveness of NIPT in average-risk pregnancies from the perspective of a provincial public payer in Canada.

Methods: A model was developed to compare traditional prenatal screening (TPS), NIPT as a second-tier test (performed only after a positive TPS result), and NIPT as a first-tier test (performed instead of TPS) for trisomies 21, 18, and 13; sex chromosome aneuploidies; and microdeletions in a hypothetical annual population cohort of average-risk pregnancies (142 000 to 148,000) in Ontario, Canada.

Comparison of the expected rewards between probabilistic and deterministic analyses in a Markov model.

: In Markov models that evaluate the cost-effectiveness of health-care technologies, it is generally recommended to use probabilistic analysis instead of deterministic analysis. We sought to compare the performance of probabilistic and deterministic analysis in estimating the expected rewards in a Markov model.: We applied Jensen's inequality to compare the expected Markov rewards between probabilistic and deterministic analysis and conducted a simulation study to compare the bias and accuracy between the two approaches.

Some issues for the evaluation of noninferiority trials.

Although published noninferiority trials (NITs) generally conclude that the experimental intervention being studied is noninferior compared with standard therapy or active control, NIT quality is often not satisfactory. We have proposed 14 questions to assist in evaluating the clinical evidence of the experimental versus standard therapy. The aim of these questions is to critically appraise NITs and support proper interpretation of study results.

A small-molecule IRF3 agonist functions as an influenza vaccine adjuvant by modulating the antiviral immune response.

Vaccine adjuvants are essential to drive a protective immune response in cases where vaccine antigens are weakly immunogenic, where vaccine antigen is limited, or where an increase in potency is needed for a specific population, such as the elderly. To discover novel vaccine adjuvants, we used a high-throughput screen (HTS) designed to identify small-molecule agonists of the RIG-I-like receptor (RLR) pathway leading to interferon regulatory factor 3 (IRF3) activation. RLRs are a group of cytosolic pattern-recognition receptors that are essential for the recognition of viral nucleic acids during infection.

Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway.

Unlabelled: The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication.

A validation study of administrative data algorithms to identify patients with Parkinsonism with prevalence and incidence trends.

Background: Epidemiological studies for identifying patients with Parkinson's disease (PD) or Parkinsonism (PKM) have been limited by their nonrandom sampling techniques and mainly veteran populations. This reduces their use for health services planning. The purpose of this study was to validate algorithms for the case ascertainment of PKM from administrative databases using primary care patients as the reference standard.

Assessing the validity of using administrative data to identify patients with epilepsy.

Objective: Previous validation studies assessing the use of administrative data to identify patients with epilepsy have used targeted sampling or have used a reference standard of patients in the neurologist, hospital, or emergency room setting. Therefore, the validity of using administrative data to identify patients with epilepsy in the general population has not been previously assessed. The purpose of this study was to determine the validity of using administrative data to identify patients with epilepsy in the general population.

Validity of administrative data for identifying patients who have had a stroke or transient ischemic attack using EMRALD as a reference standard.

Background: Surveillance for stroke/transient ischemic attack (TIA) using administrative data has traditionally been limited to reporting patients who had an acute event and were hospitalized. This underestimates the true prevalence because many events do not result in hospitalization. We examined whether the accuracy of administrative data for identifying prevalent stroke/TIA could be improved by using data from both inpatient and outpatient visits.

Isoflavone agonists of IRF-3 dependent signaling have antiviral activity against RNA viruses.

There is a growing need for novel antiviral therapies that are broad spectrum, effective, and not subject to resistance due to viral mutations. Using high-throughput screening methods, including computational docking studies and an interferon-stimulated gene 54 (ISG54)-luciferase reporter assay, we identified a class of isoflavone compounds that act as specific agonists of innate immune signaling pathways and cause activation of the interferon regulatory factor (IRF-3) transcription factor. The isoflavone compounds activated the ISG54 promoter, mediated nuclear translocation of IRF-3, and displayed highly potent activity against hepatitis C virus (HCV) and influenza virus.

Gene expression signature of c-MYC-immortalized human fibroblasts reveals loss of growth inhibitory response to TGFβ.

Cancer cells exhibit the ability to proliferate indefinitely, but paradoxically, overexpression of cellular oncogenes in primary cells can result in a rapid and irreversible cell cycle arrest known as oncogene-induced senescence (OIS). However, we have shown that constitutive overexpression of the oncogene c-MYC in primary human foreskin fibroblasts results in a population of cells with unlimited lifespan; these immortalized cells are henceforth referred to as iMYC. Here, in order to further elucidate the mechanisms underlying the immortalization process, a gene expression signature of three independently established iMYC cell lines compared to matched early passage c-MYC overexpressing cells was derived.

Epigenetic down-regulation of ARF expression is a selection step in immortalization of human fibroblasts by c-Myc.

The transcription factor c-Myc is implicated in the pathogenesis of many cancers. Among the multiple functions of c-Myc, activation of hTert and other genes involved in cellular life span contributes to its role as an oncogene. However, the ability of c-Myc to directly immortalize human cells remains controversial.