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Background and Objective: Distributional cost-effectiveness analysis (DCEA) facilitates quantitative assessments of how health effects and costs are distributed among population subgroups, and of potential trade-offs between health maximisation and equity. Implementation of DCEA is currently explored by the National Institute for Health and Care Excellence (NICE) in England. Recent research conducted an aggregate DCEA on a selection of NICE appraisals; however, significant questions remain regarding the impact of the characteristics of the patient population (size, distribution by the equity measure of interest) and methodologic choices on DCEA outcomes. Cancer is the indication most appraised by NICE, and the relationship between lung cancer incidence and socioeconomic status is well established. We aimed to conduct an aggregate DCEA of two non-small cell lung cancer (NSCLC) treatments recommended by NICE, and identify key drivers of the analysis. Methods: Subgroups were defined according to socioeconomic deprivation. Data on health benefits, costs, and target populations were extracted from two NICE appraisals (atezolizumab versus docetaxel [second-line treatment following chemotherapy to represent a broad NSCLC population] and alectinib versus crizotinib [targeted first-line treatment to represent a rarer mutation-positive NSCLC population]). Data on disease incidence were derived from national statistics. Distributions of population health and health opportunity costs were taken from the literature. A societal welfare analysis was conducted to assess potential trade-offs between health maximisation and equity. Sensitivity analyses were conducted, varying a range of parameters. Results: At an opportunity cost threshold of £30,000 per quality-adjusted life-year (QALY), alectinib improved both health and equity, thereby increasing societal welfare. Second-line atezolizumab involved a trade-off between improving health equity and maximising health; it improved societal welfare at an opportunity cost threshold of £50,000/QALY. Increasing the value of the opportunity cost threshold improved the equity impact. The equity impact and societal welfare impact were small, driven by the size of the patient population and per-patient net health benefit. Other key drivers were the inequality aversion parameters and the distribution of patients by socioeconomic group; skewing the distribution to the most (least) deprived quintile improved (reduced) equity gains. Conclusion: Using two illustrative examples and varying model parameters to simulate alternative decision problems, this study suggests that key drivers of an aggregate DCEA are the opportunity cost threshold, the characteristics of the patient population, and the level of inequality aversion. These drivers raise important questions in terms of the implications for decision making. Further research is warranted to examine the value of the opportunity cost threshold, capture the public's views on unfair differences in health, and estimate robust distributional weights incorporating the public's preferences. Finally, guidance from health technology assessment organisations, such as NICE, is needed regarding methods for DCEA construction and how they would interpret and incorporate those results in their decision making. [ABSTRACT FROM AUTHOR]

As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature. Real-world data (RWD) based control arms provide an option to compare the effectiveness of single-arm trials. By performing multiple quantitative bias analyses to alleviate concerns about trial-RWD comparability, here the authors show that the RET inhibitor pralsetinib provides survival benefit in patients with RET fusion-positive non-small cell lung cancer from the ARROW single-arm trial, (NCT03037385) when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. [ABSTRACT FROM AUTHOR]

Background: Data on cancer prevalence and incidence in multiple sclerosis (MS) patients are controversial. This study is aimed at estimating cancer risk in MS patients. Methods: Nested case–control study using data collected between 01/01/1987 and 28/02/2016 from the United Kingdom Clinical Practice Research Datalink. Cancer diagnoses after first MS code (index date) was counted in 10,204 MS patients and 39,448 controls matched by sex, age, general practitioner, and registration year. Cancer rates were compared using multivariable Cox regression models. Ethics approval was not required. Results: Cancer was reported in 433 (4.41%) MS patients and 2014 (5.31%) controls after index date. Cancer risk was associated with gender (HR for female = 0.88, 95% CI = 0.81–0.96, p = 0.004), age at index date (HR = 1.06, 95% CI = 1.06–1.07, p < 0.001), and index year (HR = 1.01, 95% CI = 1.00–1.02, p = 0.016), but not with MS status (HR = 0.95, 95% CI = 0.86–1.05, p = 0.323). A significant interaction between MS status and index year was found (HR = 1.02, 95% CI = 1.00–1.04, p = 0.022). Cancer risk was positively associated with index year among MS patients (HR = 1.03, 95% CI = 1.01–1.05; p = 0.010), but not controls (HR = 1.01, 95% CI = 0.99–1.02; p = 0.144). MS patients compared to controls had no increased risk for any specific cancer type. Conclusions: Overall cancer risk was similar in multiple sclerosis patients and matched controls. The frequency of cancer diagnoses has increased over time among MS patients but not in controls. [ABSTRACT FROM AUTHOR]

The Clinical Practice Research Datalink (CPRD) is a repository of electronic medical records collected during routine primary care clinical practice in the UK, and is one of the most widely used sources of real-world data for healthcare research. Although CPRD provides access to comprehensive longitudinal patient records, the data does not fully capture diagnoses or outcomes occurring in secondary care and/or mortality. We provide here an overview of CPRD and the potential bias when using unlinked data in certain situations. Linkage of CPRD to other datasets can help to overcome these limitations. We discuss when to consider linkage to secondary care, disease-specific data sources or the official mortality data when conducting research using CPRD data. [ABSTRACT FROM AUTHOR]

The aim of this study is to test what effect the weather may have on medications prescribed to treat Parkinson's disease. Twenty-three years of monthly time, series data was sourced from the Pharmaceutical Benefits Scheme (PBS) and the Bureau of Meteorology (BOM). Data were available for eight states and territories and their corresponding capital cities. The dependent variable was the aggregate levodopa equivalent dose (LED) for 51 Parkinson's medications identified on the PBS. Two explanatory variables of interest, temperature and solar exposure, were identified in the BOM data set. Linear and cosinor models were estimated with fixed and random effects, respectively. The prescribed LED was 4.2% greater in January and 4.5% lower in July. Statistical analysis showed that temperature was associated with the prescription of Parkinson medications. Our results suggest seasonality exists in Parkinson's disease symptoms and this may be related to temperature. Further work is needed to confirm these findings and understand the underlying mechanisms as a better understanding of the causes of any seasonal variation in Parkinson's disease may help clinicians and patients manage the disease more effectively. [ABSTRACT FROM AUTHOR]

There is little understanding of how genetic variants discovered in recent genome-wide association studies are involved in the pathogenesis of multiple sclerosis (MS). We aimed to investigate which chromatin states and cell types explain genetic risk in MS. We used genotype data from 1854 MS patients and 5164 controls produced by the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium. We estimated the proportion of phenotypic variance between cases and controls explained by cell-specific chromatin state and DNase I hypersensitivity sites (DHSs) using the Genome-wide Complex Trait Analysis software. A large proportion of variance was explained by single-nucleotide polymorphisms (SNPs) in strong enhancer (SE) elements of immortalized B lymphocytes (5.39%). Three independent SNPs located within SE showed suggestive evidence of association with MS: rs12928822 (odds ratio (OR)=0.81, 95% confidence interval (CI)=0.73-0.89, P=2.48E−05), rs727263 (OR=0.75, 95% CI=0.66-0.85, P=3.26E−06) and rs4674923 (OR=0.85, 95% CI=0.79-0.92, P=1.63E−05). Genetic variants located within DHSs of CD19+ B cells explained the greatest proportion of variance. Genetic variants influencing the risk of MS are located within regulatory elements active in immune cells. This study also identifies a number of immune cell types likely to be involved in the causal cascade and that carry important implications for future studies of therapeutic design. [ABSTRACT FROM AUTHOR]

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10-1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS), although efficient to detect genes involved in complex diseases, are not designed to measure the real effect of the genes. This is illustrated here by the example of IL2RA in multiple sclerosis (MS). Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one. This study investigates whether a pair of SNPs better explains the observed linkage and association data than a single SNP. In total, 522 trio families and 244 affected sib-pairs were typed for 26 IL2RA SNPs. For each SNP and pairs of SNPs, the phased genotypes of patients and controls were compared to determine the SNP set offering the best risk discrimination. Consistency between the genotype risks provided by the retained set and the identical by descent allele sharing in affected sib-pairs was assessed. After controlling for multiple testing, the set of SNPs rs2256774 and rs3118470, provides the best discrimination between the case and control genotype distributions (P-corrected=0.009). The relative risk between the least and most at-risk genotypes is 3.54 with a 95% confidence interval of [2.14-5.94]. Furthermore, the linkage information provided by the allele sharing between affected sibs is consistent with the retained set (P=0.80) but rejects the SNP reported in the literature (P=0.006). Establishing a valid modeling of a disease gene is essential to test its potential interaction with other genes and to reconstruct the pathophysiological pathways. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology. Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels. We review here evidence supporting a role of DBP in MS. Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase. Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression. [ABSTRACT FROM AUTHOR]

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study by the International Multiple Sclerosis Genetics Consortium (IMSGC) reported association of 17 single-nucleotide polymorphisms (SNPs) in 14 loci with multiple sclerosis (MS). Only two loci, HLA-DRA and IL2RA, reached genome-wide significance (P<5E−08). In our study, we determined whether we could replicate the results of the IMSGC and whether more SNPs are genome-wide significantly associated with MS. We assessed the association between the 17 IMSGC SNPs and MS in three cohorts (total number of subjects 3981, among these 1853 cases). We performed a meta-analysis of the results of our study, the original IMSGC results and the results of a recent replication study performed in the Australian population. Of the 17 IMSGC SNPs, five SNPs showed genome-wide significant association with MS: HLA-DRA (P=8E−124), IL7R (P=6E−09), IL2RA (P=1E−11), CD58 (P=4E−09) and CLEC16A (P=3E−12). Therefore, genome-wide significance has now been shown for SNPs in different non-HLA MS risk genes. Several of these risk genes, including CD58 and CLEC16A, are shared by different autoimmune diseases. Fine mapping studies will be needed to determine the functional contributions to distinct autoimmune phenotypes. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out. [ABSTRACT FROM AUTHOR]

The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, χ 2 = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in which the authors discuss the role of Epstein-Barr virus and gene-environment interactions in Multiple Sclerosis.

The article discuses the combined analysis related to breastfeeding and multiple sclerosis relapses. It mentions that no consensus has been reached on the impact of breastfeeding in relation to post-partum relapse risk. It mentions of a study under meta data was analyzed to give a more accurate estimate of the impact of breastfeeding on the risk of post-partum relapse.

A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case–Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values ≤0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648–0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716–0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex neurological trait. Allelic variation in the MHC class II region exerts the single strongest effect on MS genetic risk. The clinical onset of the disease is extremely variable, and can range from the first to the ninth decade of life. Epidemiological studies have suggested a modest genetic component to the age of onset (AO) of MS. Previous studies have shown that HLA-DRB1*1501 may be associated with a younger AO. Here, we sought to uncover any effect of HLA-DRB1*1501 on the AO of MS in a large Canadian cohort. A total of 1816 MS patients were genotyped for HLA-DRB1. Patients carrying HLA-DRB1*1501 were shown to have a small, but significantly lower, AO than patients without the allele (P=0.03). HLA-DRB1*1501 was also shown to reduce the mean AO in both progressive and relapsing forms of the disease. An investigation of parent-of-origin effects indicated that the lower AO for HLA-DRB1*1501 patients arises from maternally transmitted HLA-DRB1*1501 haplotypes (maternal HLA-DRB1*1501 mean AO=28.4 years, paternal=30.3 years; P=0.009). HLA-DRB1*1501 exerts a modest, but significant effect on the AO of all forms of MS. Parent-of-origin effects at the MHC are further implicated in MS disease pathogenesis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex trait in which HLA-DRB1*15 bearing MHC haplotypes increase risk of MS in people of Northern European descent. In this investigation of 7,334 individuals from 1,515 MS families, the largest cohort used to study the HLA-DRB1 locus to date, we analysed the transmission of HLA-DRB1*15 haplotypes stratified by sex of transmitting parent. A significant over transmission of HLA-DRB1*15 from mothers was observed ( χ 2 = 7.73, P = 0.0054), suggesting that parent of origin effects at the MHC determine susceptibility to MS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the ubiquity of Multiple sclerosis (MS) in immigrants of Iran to British Columbia, and Canada.

A letter to the editor is presented which discusses multiple sclerosis (MS) risk due to mother-child blood group incompatibility.

The article examines the evidence for a genetic component to male homosexuality. Some researchers performed the first genome-wide linkage scan for male homosexuality using 403 microsatellite markers. However, no evidence for linkage on chromosome 7q36 could be established as found by some researchers. It is believed that more genetic studies are required to find relative genes that can be the evidence to male homosexuality.

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10−10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus and multiple sclerosis have been largely seen as different, organ-specific diseases, which are managed by different medical specialties. Research studies on these diseases have for the most part followed independent tracks. In this Review, we highlight the latest epidemiological and genetic findings, which have identified many features common to both disorders. Experts consider it increasingly likely that the environment contributes substantially to this overlap. However, although genetic elements that are distinct to each disease probably determine the ultimate form of autoimmunity that is manifested, strikingly broad parallels are seen between the components of genetic risk of type 1 diabetes mellitus and multiple sclerosis. Similarities and differences between these two diseases draw attention to shared disease pathways but insights into each disorder are providing mutual illumination of their pathogenesis. [ABSTRACT FROM AUTHOR]