Handling Overlapping Asymmetric Datasets -- A Twice Penalized P-Spline Approach

Overlapping asymmetric datasets are common in data science and pose questions of how they can be incorporated together into a predictive analysis. In healthcare datasets there is often a small amount of information that is available for a larger number of patients such as an electronic health record, however a small number of patients may have had extensive further testing. Common solutions such as missing imputation can often be unwise if the smaller cohort is significantly different in scale to the larger sample, therefore the aim of this research is to develop a new method which can model the smaller cohort against a particular response, whilst considering the larger cohort also. Motivated by non-parametric models, and specifically flexible smoothing techniques via generalized additive models, we model a twice penalized P-Spline approximation method to firstly prevent over/under-fitting of the smaller cohort and secondly to consider the larger cohort. This second penalty is created through discrepancies in the marginal value of covariates that exist in both the smaller and larger cohorts. Through data simulations, parameter tunings and model adaptations to consider a continuous and binary response, we find our twice penalized approach offers an enhanced fit over a linear B-Spline and once penalized P-Spline approximation. Applying to a real-life dataset relating to a person's risk of developing Non-Alcoholic Steatohepatitis, we see an improved model fit performance of over 65%. Areas for future work within this space include adapting our method to not require dimensionality reduction and also consider parametric modelling methods. However, to our knowledge this is the first work to propose additional marginal penalties in a flexible regression of which we can report a vastly improved model fit that is able to consider asymmetric datasets, without the need for missing data imputation.Comment: 52 pages, 17 figures, 8 tables, 34 reference

Handling Overlapping Asymmetric Data Sets—A Twice Penalized P-Spline Approach

Aims: Overlapping asymmetric data sets are where a large cohort of observations have a small amount of information recorded, and within this group there exists a smaller cohort which have extensive further information available. Missing imputation is unwise if cohort size differs substantially; therefore, we aim to develop a way of modelling the smaller cohort whilst considering the larger. Methods: Through considering traditionally once penalized P-Spline approximations, we create a second penalty term through observing discrepancies in the marginal value of covariates that exist in both cohorts. Our now twice penalized P-Spline is designed to firstly prevent over/under-fitting of the smaller cohort and secondly to consider the larger cohort. Results: Through a series of data simulations, penalty parameter tunings, and model adaptations, our twice penalized model offers up to a 58% and 46% improvement in model fit upon a continuous and binary response, respectively, against existing B-Spline and once penalized P-Spline methods. Applying our model to an individual’s risk of developing steatohepatitis, we report an over 65% improvement over existing methods. Conclusions: We propose a twice penalized P-Spline method which can vastly improve the model fit of overlapping asymmetric data sets upon a common predictive endpoint, without the need for missing data imputation

A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH

BACKGROUND Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator–activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The pri- mary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs.33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT0300807

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory 'milieu' initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD

The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity. METHODS: The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients. RESULTS: In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)). CONCLUSIONS: Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH

Lifestyle Behavior Change in Patients With Nonalcoholic Fatty Liver Disease:A Qualitative Study of Clinical Practice

Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition worldwide and is linked largely to obesity and inactivity. Lifestyle modification is the primary treatment for NAFLD targeting dietary change, physical activity, and exercise to facilitate weight loss and weight loss maintenance. This has been shown to reduce steatosis and ameliorate steatohepatitis. European Clinical Practice Guidelines for the management of NAFLD highlight the importance of targeting lifestyle behavior change in all patients with NAFLD regardless of disease severity. These guidelines recommend combining dietary restriction and a progressive increase in aerobic exercise and resistance training with a focus on tailoring interventions to the individual patient. Practice guidelines published by the American Association for the Study of Liver Diseases recommend weight loss of at least 3% to 5% of body weight via hypocaloric diet or diet combined with increased physical activity but state that these lifestyle interventions should target patients with nonalcoholic steatohepatitis. Given the benefits of lifestyle behavior change, this study explored the perceptions surrounding clinical care as currently offered to patients with NAFLD. The aim of this study was to establish whether current provision of lifestyle behavior change support is sufficient, whether health care professionals believe they have the tools to target lifestyle behavior changes effectively, and how targeting diet and physical activity/exercise to facilitate weight loss and weight loss maintenance in practice can be improved from the perspective of health care professionals and patients

Cost of non-alcoholic steatohepatitis in Europe and the USA: the GAIN study

Background & Aims: Non-alcoholic steatohepatitis (NASH) leads to cirrhosis and is associated with a substantial socioeco- nomic burden, which, coupled with rising prevalence, is a growing public health challenge. However, there are few real-world data available describing the impact of NASH. Methods: The Global Assessment of the Impact of NASH (GAIN) study is a prevalence-based burden of illness study across Europe (France, Germany, Italy, Spain, and the UK) and the USA. Physicians provided demographic, clinical, and economic patient information via an online survey. In total, 3,754 patients found to have NASH on liver biopsy were stratified by fibrosis score and by biomarkers as either early or advanced fibrosis. Per-patient costs were estimated using national unit price data and extrapolated to the population level to calculate the economic burden. Of the patients, 767 (20%) provided information on indirect costs and health-related quality of life using the EuroQOL 5-D (EQ-5D; n = 749) and Chronic Liver Disease Ques- tionnaire – Non-Alcoholic Fatty Liver Disease (CLDQ-NAFLD) (n = 723). Results: Mean EQ-5D and CLDQ-NAFLD index scores were 0.75 and 4.9, respectively. For 2018, the mean total annual per patient cost of NASH was V2,763, V4,917, and V5,509 for direct medical, direct non-medical, and indirect costs, respectively. National per-patient cost was highest in the USA and lowest in France. Costs increased with fibrosis and decompensation, driven by hospitalisation and comorbidities. Indirect costs were driven by work loss. Conclusions: The GAIN study provides real-world data on the direct medical, direct non-medical, and indirect costs asso- ciated with NASH, including patient-reported outcomes in Europe and the USA, showing a substantial burden on health services and individuals