Mediational g-formula for time-varying treatment and repeated-measured multiple mediators: Application to atorvastatin’s effect on cardiovascular disease via cholesterol lowering and anti-inflammatory actions in elderly type 2 diabetics

2021 ◽  
pp. 096228022110259
Author(s):  
Shintaro Yamamuro ◽  
Tomohiro Shinozaki ◽  
Satoshi Iimuro ◽  
Yutaka Matsuyama

Modern causal mediation theory has formalized several types of indirect and direct effects of treatment on outcomes regarding specific mediator variables. We reviewed and unified distinct approaches to estimate the “interventional” direct and indirect effects for multiple mediators and time-varying variables. This study was motivated by a clinical trial of elderly type-2 diabetic patients in which atorvastatin was widely prescribed to control patients’ cholesterol levels to reduce diabetic complications, including cardiovascular disease. Among atorvastatin’s preventive side-effects (pleiotropic effects), we focus on its anti-inflammatory action as measured by white blood cell counts. Hence, we estimate atorvastatin’s interventional indirect effects through cholesterol lowering and through anti-inflammatory action, and interventional direct effect bypassing these two actions. In our analysis, total effect (six-year cardiovascular disease risk difference) estimated by standard plug-in g-formula of −3.65% (95% confidence interval: −10.29%, 4.38%) is decomposed into indirect effect via low-density lipoprotein cholesterol (−0.90% [−1.91%, −0.07%]), via white blood cell counts (−0.03% [−0.22%, 0.11%]), and direct effect (−2.84% [−9.71%, 5.41%]) by the proposed parametric mediational g-formula. The SAS program and its evaluation via simulated datasets are provided in the Supplemental materials.

1996 ◽  
Vol 76 (02) ◽  
pp. 184-186 ◽  
Author(s):  
Kenji lijima ◽  
Fumiyo Murakami ◽  
Yasushi Horie ◽  
Katsumi Nakamura ◽  
Shiro Ikawa ◽  
...  

SummaryA 74-year-old female developed pneumonia following herpes simplex encephalitis. Her white blood cell counts reached 28,400/μl, about 90% of which consisted of granulocytes. The polymorphonuclear (PMN) elastase/α1-arantitrypsin complex levels increased and reached the maximum of 5,019 ng/ml, indicating the release of a large amount of elastase derived from the granulocytes. The mechanism of PMN elastase release was most likely to be granulocyte destruction associated with phagocytosis. The cleavage of fibrinogen and fibrin by PMN elastase, independent of plasmin, was indicated by the presence of the fragments in immunoprecipitated plasma from the patient corresponding to elastase-induced FDP D and DD fragments and the absence of fragments corresponding to plasmin-induced FDP D and DD fragments on SDS-PAGE. These findings suggested that the large amount of PMN elastase released from the excessive numbers of granulocytes in this patient with herpes simplex encephalitis and pneumonia, induced the cleavage of fibrinogen and fibrin without the participation of plasmin.


2016 ◽  
Vol 97 (6) ◽  
pp. 511-516 ◽  
Author(s):  
Veronika Buxhofer‐Ausch ◽  
Michael Steurer ◽  
Siegfried Sormann ◽  
Ernst Schloegl ◽  
Wolfgang Schimetta ◽  
...  

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e58354 ◽  
Author(s):  
Nancy Babio ◽  
Núria Ibarrola-Jurado ◽  
Mònica Bulló ◽  
Miguel Ángel Martínez-González ◽  
Julia Wärnberg ◽  
...  

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