An application of Multiple Imputation under the Two Generalized Parametric Families

Abstract In forestry, the variable of interest is not always directly available from forest inventories. Consequently, practitioners have to rely on models to obtain predictions of this variable of interest. This context leads to hybrid inference, which is based on both the probability design and the model. Unfortunately, the current analytical hybrid estimators for the variance of the point estimator are mainly based on linear or nonlinear models and their use is limited when the model reaches a high level of complexity. An alternative consists of using a variance estimator based on resampling methods (Rubin, D. B. (1987). Multiple imputation for nonresponse surveys. John Wiley & Sons, Hoboken, New Jersey, USA). However, it turns out that a parametric bootstrap (BS) estimator of the variance can be biased in contexts of hybrid inference. In this study, we designed and tested a corrected BS estimator for the variance of the point estimator, which can easily be implemented as long as all of the stochastic components of the model can be properly simulated. Like previous estimators, this corrected variance estimator also makes it possible to distinguish the contribution of the sampling and the model to the variance of the point estimator. The results of three simulation studies of increasing complexity showed no evidence of bias for this corrected variance estimator, which clearly outperformed the BS variance estimator used in previous studies. Since the implementation of this corrected variance estimator is not much more complicated, we recommend its use in contexts of hybrid inference based on complex models.

Download Full-text

P189 Comparison of secukinumab versus adalimumab efficacy on skin outcomes in psoriatic arthritis: 52-week results from the EXCEED study

Rheumatology ◽

10.1093/rheumatology/keab247.184 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Alice Gottlieb ◽

Frank Behrens ◽

Peter Nash ◽

Joseph F Merola ◽

Pascale Pellet ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Missing Data ◽

Multiple Imputation ◽

Plaque Psoriasis ◽

Stock Ownership ◽

Research Support ◽

Acr20 Response ◽

Number Of Patients ◽

Pasi Score ◽

To Receive

Abstract Background/Aims Psoriatic arthritis (PsA) is a heterogeneous disease comprising musculoskeletal and dermatological manifestations, especially plaque psoriasis. Secukinumab, an interleukin17A inhibitor, provided significantly greater PASI75/100 responses in two head-to-head trials versus etanercept or ustekinumab, a tumour necrosis factor inhibitor (TNFi), in patients with moderate-to-severe plaque psoriasis. The EXCEED study (NCT02745080) investigated whether secukinumab was superior to adalimumab, another TNFi, as monotherapy in biologic-naive active PsA patients with active plaque psoriasis (defined as having ≥1 psoriatic plaque of ≥ 2 cm diameter, nail changes consistent with psoriasis or documented history of plaque psoriasis). Here we report the pre-specified skin outcomes from the EXCEED study in the subset of patients with ≥3% body surface area (BSA) affected with psoriasis at baseline. Methods In this head-to-head, Phase 3b, randomised, double-blind, active-controlled, multicentre, parallel-group trial, patients were randomised to receive subcutaneous secukinumab 300 mg at baseline and Weeks 1-4, followed by dosing every 4 weeks until Week 48, or subcutaneous adalimumab 40 mg at baseline followed by the same dosing every 2 weeks until Week 50. The primary endpoint was superiority of secukinumab versus adalimumab on ACR20 response at Week 52. Pre-specified outcomes included the proportion of patients achieving a combined ACR50 and PASI100 response, PASI100 response, and absolute PASI score ≤3. Missing data were handled using multiple imputation. Results Overall, 853 patients were randomised to receive secukinumab (n = 426) or adalimumab (n = 427). At baseline, 215 and 202 patients had at least 3% BSA affected with psoriasis in the secukinumab and adalimumab groups, respectively. At Week 52, more patients achieved simultaneous improvement in ACR50 and PASI100 response with secukinumab versus adalimumab (30.7% versus 19.2%, respectively; P = 0.0087). Greater efficacy was demonstrated for secukinumab versus adalimumab for PASI100 responses and for the proportion of patients achieving absolute PASI score ≤3 (Table 1). Conclusion In this pre-specified analysis, secukinumab provided higher responses compared with adalimumab in achievement of combined improvement in joint and skin disease (combined ACR50 and PASI100 response) and in skin-specific endpoints (PASI100 and absolute PASI score ≤3) at Week 52. P189 Table 1:Skin-specific outcomes at Week 52Endpoints, % responseSEC 300 mg (N = 215)ADA 40 mg (N = 202)P value (unadjusted)PASI10046300.0007Combined ACR50 and PASI10031190.0087Absolute PASI score ≤379650.0015P value vs ADA; unadjusted P values are presented. Multiple imputation was used for handling missing data. ADA, adalimumab; ACR, American College of Rheumatology; N, number of patients in the psoriasis subset; PASI, Psoriasis Area and Severity Index; SEC, secukinumab. Disclosure A. Gottlieb: Grants/research support; A.G. has received research support, consultation fees or speaker honoraria from Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB. F. Behrens: Consultancies; F.B. is a consultant for Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer Ingelheim, Janssen, MSD, Celgene, Roche and Chugai. Grants/research support; F.B. has received grant/research support from Pfizer, Janssen, Chugai, Celgene, Lilly and Roche. P. Nash: Consultancies; P.N. is a consultant for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc., Roche, Sanofi and UCB. Member of speakers’ bureau; for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc., Roche, Sanofi and UCB. Grants/research support; P.N. has received research support from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi and UCB. J. Merola: Consultancies; J.F.M. is a consultant for Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma. P. Pellet: Corporate appointments; P.P. is an employee of Novartis. Shareholder/stock ownership; P.P. is a shareholder of Novartis. L. Pricop: Corporate appointments; L.P. is an employee of Novartis. Shareholder/stock ownership; L.P. is a shareholder of Novartis. I. McInnes: Consultancies; I.M. is a consultant for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer and UCB. Grants/research support; I.M. has received grant/research support from Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen and UCB.

Download Full-text

Using multiple imputation to classify potential outcomes subgroups

Statistical Methods in Medical Research ◽

10.1177/09622802211002866 ◽

2021 ◽

pp. 096228022110028

Author(s):

Yun Li ◽

Irina Bondarenko ◽

Michael R Elliott ◽

Timothy P Hofer ◽

Jeremy MG Taylor

Keyword(s):

Multiple Imputation ◽

Statistical Methods ◽

The United States ◽

Treatment Selection ◽

Potential Outcomes ◽

Model Framework ◽

Medical Tests ◽

Gene Assay ◽

The Impact ◽

Test Result

With medical tests becoming increasingly available, concerns about over-testing, over-treatment and health care cost dramatically increase. Hence, it is important to understand the influence of testing on treatment selection in general practice. Most statistical methods focus on average effects of testing on treatment decisions. However, this may be ill-advised, particularly for patient subgroups that tend not to benefit from such tests. Furthermore, missing data are common, representing large and often unaddressed threats to the validity of most statistical methods. Finally, it is often desirable to conduct analyses that can be interpreted causally. Using the Rubin Causal Model framework, we propose to classify patients into four potential outcomes subgroups, defined by whether or not a patient’s treatment selection is changed by the test result and by the direction of how the test result changes treatment selection. This subgroup classification naturally captures the differential influence of medical testing on treatment selections for different patients, which can suggest targets to improve the utilization of medical tests. We can then examine patient characteristics associated with patient potential outcomes subgroup memberships. We used multiple imputation methods to simultaneously impute the missing potential outcomes as well as regular missing values. This approach can also provide estimates of many traditional causal quantities of interest. We find that explicitly incorporating causal inference assumptions into the multiple imputation process can improve the precision for some causal estimates of interest. We also find that bias can occur when the potential outcomes conditional independence assumption is violated; sensitivity analyses are proposed to assess the impact of this violation. We applied the proposed methods to examine the influence of 21-gene assay, the most commonly used genomic test in the United States, on chemotherapy selection among breast cancer patients.

Download Full-text