A Unified Survey of Treatment Effect Heterogeneity Modelling and Uplift Modelling

A central question in many fields of scientific research is to determine how an outcome is affected by an action, i.e., to estimate the causal effect or treatment effect of an action. In recent years, in areas such as personalised healthcare, sociology, and online marketing, a need has emerged to estimate heterogeneous treatment effects with respect to individuals of different characteristics. To meet this need, two major approaches have been taken: treatment effect heterogeneity modelling and uplifting modelling. Researchers and practitioners in different communities have developed algorithms based on these approaches to estimate the heterogeneous treatment effects. In this article, we present a unified view of these two seemingly disconnected yet closely related approaches under the potential outcome framework. We provide a structured survey of existing methods following either of the two approaches, emphasising their inherent connections and using unified notation to facilitate comparisons. We also review the main applications of the surveyed methods in personalised marketing, personalised medicine, and sociology. Finally, we summarise and discuss the available software packages and source codes in terms of their coverage of different methods and applicability to different datasets, and we provide general guidelines for method selection.

The Impacts of Long-Term Care Insurance on Health Care Utilization and Expenditure: Evidence From China

Long-term care insurance (LTCI) is one of the important institutional responses to the growing care needs of the ageing population. Although previous studies have evaluated the impacts of LTCI on health care utilization and expenditure in developed countries, whether such impacts exist in developing countries is unknown. The Chinese government has initiated policy experimentation on LTCI to cope with the growing and unmet need for aged care. Employing a quasi-experiment design, this study aims to examine the policy treatment effect of LTCI on health care utilization and out-of-pocket health expenditure in China. The Propensity Score Matching with Difference-in-difference approach was used to analyse the data obtained from four waves of China Health and Retirement Longitudinal Study (CHARLS). Our findings indicated that, in the aspect of health care utilization, the introduction of LTCI significantly reduced the number of outpatient visits by 0.322 times (p<0.05), the number of hospitalizations by 0.158 times (p<0.01), and the length of inpatient stay during last year by 1.441 days (p<0.01). In the aspect of out-of-pocket health expenditure, we found that LTCI significantly reduced the inpatient out-of-pocket health expenditure during last year by 533.47 yuan (p<0.01), but it did not exhibit an impact on the outpatient out-of-pocket health expenditure during last year. LTCI also had a significantly negative impact on the total out-of-pocket health expenditure by 512.56 yuan. These results are stable in the robustness tests. Considering the evident policy treatment effect of LTCI on health care utilization and out-of-pocket health expenditure, the expansion of LTCI could help reduce the needs for health care services and contain the increases in out-of-pocket health care expenditure in China.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Changes of Serum Ferritin, Hemoglobin, and Serum Iron (SI) and Treatment Effect of Iron Proteinsuccinylate Oral Solution Combined with Vitamin A and D Drops on Children with Nutritional Iron Deficiency Anemia

Objective. The purpose was to evaluate the treatment effect of iron proteinsuccinylate oral solution combined with vitamin A and D drops on children with nutritional iron deficiency anemia. Methods. 124 children treated in the outpatient department of our hospital from January 2017 to January 2020 were selected as the study subjects. They were randomly divided into control and observation two groups. The control group was treated with iron proteinsuccinylate oral solution (1.5 mL/kg) in the morning and evening, respectively. The observation group received adjuvant treatment with oral vitamin A and D drops based on the treatment of the control group. The treatment effect of proteinsuccinylate oral solution combined with vitamin A and D drops was evaluated by the serum iron (SI), serum ferritin (SF), and transferrin (TRF) levels, the values of CD3+, CD4+, and CD4+/CD8+, and other evaluation indicators. Results. After treatment, the SI and SF levels of children in both groups significantly increased ( P < 0.01 ) while the TRF level significantly decreased ( P < 0.01 ), and the SI and SF levels in the observation group increased more significantly, and the TRF level decreased more significantly compared with those in the control group ( P < 0.01 ). After treatment, the values of CD3+, CD4+, and CD4+/CD8+ of children in both groups significantly increased compared with those before treatment ( P < 0.01 ), and the values of CD3+, CD4+, and CD4+/CD8+ increased more significantly in the observation group compared with those in the control group ( P < 0.01 ). In addition, the evaluation results of treatment effect showed that the markedly effective rate in the observation group was significantly higher than that in the control group ( P < 0.01 ). Conclusion. Iron proteinsuccinylate oral solution combined with vitamin A and D drops can better improve the anemia symptoms in children, with high application value.

Beneficial Impact of Pork Dry-Cured Ham Consumption on Blood Pressure and Cardiometabolic Markers in Individuals with Cardiovascular Risk

Background: Evidence suggests that bioactive peptides reduce hypertension and affect certain metabolic pathways. Methods: Fifty-four volunteers with stage 1 prehypertension and/or hypercholesterolemia and/or basal glucose >100 mg/dL were recruited and randomized to pork dry-cured ham (n = 35) or cooked ham (placebo group; n = 19) for 28 days. After a wash-out period, meat products were changed for 28 additional days. Bioactive peptides composition and enzyme inhibitory activities of both products were characterized. Treatment comparisons for the main effects were made using a two (treatment) × two (times) repeated measures minus the effect of cooked ham (placebo). Results: 24 h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (treatment effect, p = 0.0382 y p = 0.0233, respectively) as well as the number of systolic pressure measures > 135 mmHg (treatment effect, p = 0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p = 0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p > 0.05). However, a significant rise of ghrelin levels was observed (treatment effect, p = 0.0350), while leptin plasma values slightly decreased (treatment effect, p = 0.0628). Conclusions: This study suggested the beneficial effects of regular dry-cured ham consumption on the improvement of systolic/diastolic blood pressures and facilitated the maintenance of metabolic pathways, which may be beneficial in the primary prevention of cardiovascular disease.

Safety and Efficacy of Tenecteplase in Older Patients With Large Vessel Occlusion: A Pooled Analysis of the EXTEND-IA TNK Trials

Background and Objectives:Detailed study of tenecteplase (TNK) in patients greater than 80 years of age is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients greater than 80 years with large vessel occlusion.Methods:A pooled analysis of the EXTEND-IA TNK randomized controlled trials (n=502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25mg/kg, TNK 0.40mg/kg, and alteplase 0.90mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin scale (mRS), all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIHSS, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.Results:In patients >80 years (n=137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs. 4, adjusted common OR=2.70, 95% CI: 1.23-5.94) and reduced mortality (aOR=0.34, 95% CI: 0.13-0.91) versus 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs. 4, acOR=2.28, 95% CI: 1.03-5.05) versus alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, one patient treated with alteplase and zero patients treated with TNK 0.25 mg/kg. In patients ≤ 80 years, no differences in 90-day mRS, mortality, or symptomatic ICH was observed between TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg.Conclusions:TNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients greater than 80 years of age. No differences between the doses were observed in younger patients.Classification of Evidence:This study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.Trial Registration:ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493https://www.clinicaltrials.gov/ct2/show/NCT02388061https://www.clinicaltrials.gov/ct2/show/NCT03340493