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Lipids Standardization and DAGsEnrique Schisterman, PhDEpidemiology Branch – DESPR – NICHD
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Background PCBs are lipophilic xenobiotics
Literature on exposure to PCBs is conflicting
Poses challenges for interpretation of potential health risks
Differences in laboratory practices may account for some of the equivocal findings
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Background Limited understanding of the true relations between:
Serum and adipose tissue concentrations of PCBs
Serum PCBs and serum lipids
Which in turn makes model specification difficult
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Background Investigators typically make assumptions about the
relation between serum lipids and serum PCBs expressing PCB measurements as:
Wet-weight (PCB per unit serum)
Lipid-standardization value (PCB concentration per unit lipids)
Adjusted model (Lipids are separate term)
Two-stage analysis (Lipids are regressed on PCBs with residuals entered as individual risk factors)
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Lipid Standardization The various strategies for handling serum lipids imply
different causal pathways
What is considered best practice in the lab may have an unintended impact on data analysis
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Objectives Describe 4 proposed approaches for handling serum
lipids
Show the impact of different common statistical modeling approaches on risk estimates
Evaluate the bias under a range of plausible causal systems
Determine which model best reflects underlying causal assumptions
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Proposed Approach 1 Unadjusted: Wet-weight values
PCBs per unit serum
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Proposed Approach 2 Lipid Standardization
PCB concentration per unit of lipids
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Proposed Approach 3 Adjusted
Lipids is a separate term
Lipids is a predictor/potential confounder
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Proposed Approach 4 Two-stage model
Lipids are regressed on PCBs with residuals entered as individual risk factors
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Proposed Approaches Unadjusted: Wet-weight values
Lipid Standardized
Adjusted
Two-Stage
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Simulation Study To evaluate the impact of these approaches for handling
serum lipids in models on risk estimates, Schisterman et al. simulated data from a log normal distribution to determine bias
They varied: True underlying causal relations Statistical model used for risk estimates Relation between PCBs and serum lipids Measurement error in serum lipids
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DAG A: Simple cause & effect PCBS causes Y, Lipids unrelated
PCBS Y
Lipids
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DAG A: Simple cause & effect PCBS causes Y, Lipids unrelated
PCBS Y
Lipids
Model logit(Y)=… % BiasUnadjusted PCBS -0.8
Standardized PCBS / Lipids -75.9
Adjusted PCBS + Lipids -0.7
Two-stage PCBS + Residuals -0.714
DAG A: Simple cause & effect PCBS causes Y, Lipids unrelated
PCBS Y
Lipids
Model logit(Y)=… % BiasUnadjusted PCBS -0.8
Standardized PCBS / Lipids -75.9
Adjusted PCBS + Lipids -0.7
Two-stage PCBS + Residuals -0.715
DAG A: Extensions
PCBS Y
Lipids
PCBS Y
Lipids
1
PCBS Y
Lipids
PCBS Y
LipidsA
2 3
Model A 1 2 3
Unadjusted -0.8 1.2 0.4 -0.4Standardized -75.9 -51.3 -79.8 -85.0Adjusted -0.7 1.8 0.8 -0.1Two-stage -0.7 1.8 0.5 -0.3
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DAG B: Confounding U causes PCBS and Lipids, both cause Y
PCBS Y
LipidsU
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DAG B: Confounding U causes PCBS and Lipids, both cause Y
PCBS Y
LipidsU
Model logit(Y)=… % BiasUnadjusted PCBS 24.0
Standardized PCBS / Lipids -128.8
Adjusted PCBS + Lipids 0.1
Two-stage PCBS + Residuals 27.218
DAG B: Extensions
Model B 1 2
Unadjusted 24.0 -15.4 -11.2Standardized -128.8 -351.3 -128.3Adjusted 0.1 -99.4 -25.4Two-stage 27.2 1.1 -8.7
PCBS Y
Lipids
PCBS Y
Lipids
1
PCBS Y
Lipids
2
A
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DAG B: Extensions
PCBS Y
Lipids
PCBS Y
Lipids
1
PCBS Y
Lipids
2
Model B 1 2
Unadjusted 24.0 -15.4 -11.2Standardized -128.8 -351.3 -128.3Adjusted 0.1 -99.4 -25.4Two-stage 27.2 1.1 -8.7
A
Overadjustment
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DAG C: PCBS per Lipids as Ascending Proxy PCB in adipose tissue causes PCB in serum per lipids, and
causes Y PCBS/Lipids Y
PCBA
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DAG C: PCBS per Lipids as Ascending Proxy PCB in adipose tissue causes PCB in serum per lipids, and
causes Y PCBS/Lipids Y
PCBA
Model logit(Y)=… % BiasUnadjusted PCBS -86.3
Standardized PCBS / Lipids -1.0
Adjusted PCBS + Lipids -1.0
Two-stage PCBS + Residuals -85.922
Summary of Bias by DAG
DAG Type UnadjustedStandardiz
edAdjusted Two-stage
A
Cause & Effect
-0.8 -75.9 -0.7 -0.7A1 1.2 -51.3 1.8 1.8A2 0.4 -79.8 0.8 0.5A3 -0.4 -85 -0.1 -0.3
BConfoundin
g24 -129 0.1 27.2
B1 Intermediate
-15.4 -351 -99.4 1.1B2 -11.2 -128 -25.4 -8.7C PCBs/Lipids -86.3 -1 -1 -85.9
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Summary Evaluated 4 statistical models commonly used to assess
the effects of PCBs (or other lipophilic environmental contaminants) on human health
Each model showed minimal bias for at least the causal truth for which it was ideally suited Bias ranged from -351% to 24% Standardized model produced large biases for most of the
evaluated DAGs The adjusted model produced small biases even for the DAG
for which standardization is optimal
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Limitations Only considered DAGs with 2 to 4 factors
Including additional factors necessarily makes evaluation more complex and the trade-off between efficiency and robustness more important
Though in their simulation the adjusted model produced consistently unbiased estimates, there are situations where adjustment should be avoided Collider Common cause
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Conclusion Simulations demonstrate that statistical models that fail
to uphold the underlying causal assumptions lead to biased results This bias can have negative implications on the interpretation
of effects of exposures on human health end points
Investigators must consider biology, biologic medium, laboratory measurement, and other underlying modeling assumptions when devising a statistical model
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References Schisterman EF, Whitcomb BW, Buck Louis GM, Louis TA.
Lipid Adjustment in the Analysis of Environmental Contaminants and Human Health Risks. Environmental Health Perspectives 2005;113(7):853-7.
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