Is the price right? Paying for value today to get more value tomorrow.

BACKGROUND: Contemporary debates about drug pricing feature several widely held misconceptions, including the relationship between incentives and innovation, the proportion of total healthcare spending on pharmaceuticals, and whether the economic evaluation of a medicine can be influenced by things other than clinical efficacy. MAIN BODY: All citizens should have access to timely, equitable, and cost-effective care covered by public funds, private insurance, or a combination of both. Better managing the collective burden of diseases borne by today's and future generations depends in part on developing better technologies, including better medicines. As in any innovative industry, the expectation of adequate financial returns incentivizes innovators and their investors to develop new medicines. Estimating expected returns requires that they forecast revenues, based on the future price trajectory and volume of use over time. How market participants decide what price to set or accept can be complicated, and some observers and stakeholders want to confirm whether the net prices society pays for novel medicines, whether as a reward for past innovation or an incentive for future innovation, are commensurate with those medicines' incremental value. But we must also ask "value to whom?"; medicines not only bring immediate clinical benefits to patients treated today, but also can provide a broad spectrum of short- and long-term benefits to patients, their families, and society. Spending across all facets of healthcare has grown over the last 25 years, but both inpatient and outpatient spending has outpaced drug spending growth even as our drug armamentarium is constantly improving with safer and more effective medicines. In large part, this is because, unlike hospitals, drugs typically go generic, thus making room in our budgets for new and better ones, even as they often keep patients out of hospitals, driving further savings. CONCLUSION: A thorough evaluation of drug spending and value can help to promote a better allocation of healthcare resources for both the healthy and the sick, both of whom must pay for healthcare. Taking a holistic approach to assessing drug value makes it clear that a branded drug's value to a patient is often only a small fraction of the drug's total value to society. Societal value merits consideration when determining whether and how to make a medicine affordable and accessible to patients: a drug that is worth its price to society should not be rendered inaccessible to ill patients by imposing high out-of-pocket costs or restricting coverage based on narrow health technology assessments (HTAs). Furthermore, recognizing the total societal cost of un- or undertreated conditions is crucial to gaining a thorough understanding of what guides the biomedical innovation ecosystem to create value for society. It would be unwise to discourage the development of new solutions without first appreciating the cost of leaving the problems unsolved.

Consistency of recording of chemotherapy cycles in the National Cancer Registration and Analysis Service Systemic Anti-Cancer Therapy database and the Hospital Episode Statistics Admitted Patient Care database.

Aim: We assessed the extent to which chemotherapy cycles recorded in Hospital Episode Statistics (HES) Admitted Patient Care (APC) were captured in National Cancer Registration & Analysis Service Systemic Anti-Cancer Therapy (SACT) for a cohort of lung cancer patients. Methods: All chemotherapy cycles recorded for linkage eligible lung cancer patients with a National Cancer Registration & Analysis Service diagnosis between 2012 and 2015 were identified in HES APC and SACT. Results: Among a population of 4070 lung cancer patients, 6076 chemotherapy cycles were observed in HES APC data. A total of 61% of cycles were recorded in SACT on the same day, 8% on a different day and 31% were not recorded in SACT. Conclusion: Our results suggest that SACT may not capture all chemotherapy cycles administered to a patient between 2012 and 2016; however, administrative changes mean data after this period may be more complete.

Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease.

Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

Prodromal symptoms of multiple sclerosis in primary care.

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Prevalence of Anti-JC Virus Antibody Seropositivity in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: The John Cunningham virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy. Anti-JCV antibody seropositivity is an important consideration in patients with multiple sclerosis (MS). The reported prevalence of JCV in MS patients has been conflicting. OBJECTIVE: We aimed to conduct a systematic review and meta-analysis to estimate the pooled prevalence of anti-JCV antibody seropositivity in cases with MS. METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, ProQuest, Google Scholar, and gray literature including reference of included studies, and conference abstracts which were published up to April 2019. Two independent researchers independently assessed the articles. RESULTS: The literature search found 181 articles. After eliminating duplicates, reviews, case reports, and trials, 15 articles remained. Finally, 8 articles were included for the final analysis (from Asia, Europe, the USA, and Canada). In total, 16,041 MS cases were analyzed. The prevalence of anti-JCV antibody seropositivity varied between 40 and 80%, and the pooled estimate was calculated as 60% (95% CI: 56-64%), though with significant heterogeneity (I2 = 95%, p = 0.01). CONCLUSION: The prevalence of anti-JCV antibody seropositivity is variable among MS patients in different countries, and the pooled estimate showed that this is 60% overall.

Age at menarche and risk of multiple sclerosis (MS): a systematic review and meta-analysis.

BACKGROUND: Some studies have looked at the age at menarche and risk of Multiple Sclerosis (MS).We aimed to conduct a systematic review and meta-analysis to estimate a pooled odds ratio of developing MS by increasing age at menarche. METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, google scholar and gray literature (references of references, congress abstracts) up to 10th April 2019. RESULTS: The literature search found 312 articles. After eliminating duplicates, reviews, case reports and trials, 18 articles remained. Three articles were ultimately included in the final analysis. Two studies were from Iran, and one from Canada. The pooled odds ratio (OR) for increasing 1 year of age at menarche was 0.88 (95% CI:0.82-0.94), with no significant heterogeneity (I2 = 49%, p = 0.1). Mean age at menarche was significantly different between case and control groups (mean difference = - 0.22, 95% CI = -0.42,-0.02). CONCLUSION: The result of this systematic review showed that the risk of MS decreases by increasing age at menarche.

Automated extraction of treatment patterns from social media posts: an exploratory analysis in renal cell carcinoma.

Aim: The use of health-related social media forums by patients is increasing and the size of these forums creates a rich record of patient opinions and experiences, including treatment histories. This study aimed to understand the possibility of extracting treatment patterns in an automated manner for patients with renal cell carcinoma, using natural language processing, rule-based decisions, and machine learning. Patients & methods: Obtained results were compared with those from published observational studies. Results: 42 comparisons across seven therapies, three lines of treatment, and two-time periods were made; 37 of the social media estimates fell within the variation seen across the published studies. Conclusion: This exploratory work shows that estimating treatment patterns from social media is possible and generates results within the variation seen in published studies, although further development and validation of the approach is needed.

Suspected cancer symptoms and blood test results in primary care before a diagnosis of lung cancer: a case-control study.

Aim: To compare symptoms and blood test results prior to cancer diagnosis in individuals who developed lung cancer and those who did not. Patients & methods: Nested case-control study, lung cancer patients were matched to up four controls with no record of cancer. Differences in symptoms and blood test results were investigated in the 2-year period prior to diagnosis. Results: 26,379 lung cancer patients were matched to 92,125 controls. Elevated C-reactive protein (CRP) was independently predictive of lung cancer at every 2-month interval 12 months prior to diagnosis. Elevated CRP in conjunction with at least one symptom was associated with greater than fourfold higher odds of lung cancer. Conclusion: CRP may be a prediagnostic marker for lung cancer, and when present with other symptoms could facilitate the investigation of high-risk individuals.

Performing studies using the UK Clinical Practice Research Datalink: to link or not to link?

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.

DNase hypersensitive sites and association with multiple sclerosis.

Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.

Real-world data in the United Kingdom: opportunities and challenges.

Real-world data is that collected outside the constraints of controlled clinical trials and is increasingly informing decision-making in healthcare. The landscape of real-world data in the United Kingdom is set to evolve over the coming months as the government plans to build on databases currently in place by collecting patient data from all family practices and linking this information with hospital records. This initiative, called care.data, has the potential to be an invaluable resource. However, the programme has been criticized on grounds of data privacy, which has led to an extended delay in its implementation and the expectation that a large number of people will opt out. Opt-outs may introduce substantial biases to the dataset, and understanding how to account for these presents a significant challenge for researchers. For the scope and quality of real-world evidence in the United Kingdom to be realised, and for this information to be used effectively, it is essential to address this challenge.

Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans.

A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases.

Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.

The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.

Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies.

BACKGROUND: Uric acid has antioxidant effects on neurons. Abnormally high levels of uric acid are, however, associated with gout. Previous studies have suggested that high levels of uric acid (and the presence of gout) may exert a protective effect against the risk of developing some neurological diseases. We aimed to investigate this hypothesis in a large database of hospital admissions in England. METHODS: We analysed a database of linked statistical records of hospital admissions and death registrations in England (1999-2012). A cohort of people with gout was constructed and followed for development of multiple sclerosis (MS), Parkinson's disease (PD) or motor neuron disease (MND). Then, conversely, cohorts of all people in the database with MS, PD or MND were constructed and followed for subsequent gout. Rate ratios (RRs) were determined, comparing these cohorts with people in a reference cohort. RESULTS: In the gout cohort, we observed a modest elevation of the overall risk of subsequent MS, PD and MND (respectively, RR = 1.27 (95% confidence interval 1.03-1.55), 1.11 (1.05-1.17) and 1.28 (1.11-1.48) which was largely attributable to an increased risk observed in the early years after hospitalisation for gout. The increased risk of neurological disease did not remain after 5 years. In the cohorts of people with MS or PD, there was a significantly reduced risk of subsequent gout admission (RR = 0.79 (0.69-0.89) and 0.83 (0.79-0.87), respectively). This inverse association was sustained over time. There was also a reduced risk of MND following gout which only emerged more than five years following initial gout admission (RR at 5+ years 0.35 (0.15-0.68)). CONCLUSIONS: This study investigated the epidemiological evidence for a protective role of high serum concentration of uric acid, for which we used gout as a proxy, in the aetiology of MS, PD or MND. Our observations do not support this hypothesis. However, when the order was reversed, and we retrospectively followed up patients with MS, PD and MND for a number of years, we found a statistically significant deficit of gout. This suggests that there is relationship between some aspects of these neurodegenerative diseases and metabolism of uric acid.

Vitamin D receptor binding, chromatin states and association with multiple sclerosis.

Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE (P < 2.0e-05) and 63.41-fold enrichment for AP (P < 2.0e-05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells (P < 2.0e-05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P < 2.0e-05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system.

Regulatory genomic regions active in immune cell types explain a large proportion of the genetic risk of multiple sclerosis.

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.

Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing-remitting multiple sclerosis.

BACKGROUND: Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ. OBJECTIVE: The objective of this paper is to investigate the relationship between lesion-to-ventricle (LV) distance and persistence of new BHs. METHODS: We analysed the magnetic resonance images (MRIs) of 289 relapsing-remitting (RR) MS patients, obtained during a multi-centre, placebo-controlled phase II trial over one year. RESULTS: Overall, 112/289 patients showed 367 new BHs at the beginning of the trial. Of these, 225 were located in 94/112 patients at the level of the lateral ventricles on axial MRIs and included in this analysis. In total, 86/225 (38%) BHs persisted at month 12. LV distance in persistent BHs (PBHs) was not longer than in transient BHs. In fact PBHs tended to be closer to the SVZ than transient BHs. A generalised linear mixed multivariate model adjusted for BHs clustered within a patient and including patient- as well as lesion-specific factors revealed size, ring contrast enhancement, and shorter LV distance as independent predictors for BH persistence. CONCLUSION: Location of BHs close to the lateral ventricles does not appear to favourably influence the resolution of new BHs in RRMS.