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Adjustment for Urinary Creatinine or Serum Lipids for Analytes Assayed in Pooled Specimens.

ABSTRACT: BACKGROUND:For case-control studies, pooling biologic specimens (cases with cases and controls with controls) can make it affordable to study a biomarker that is expensive to assay, while conserving quantities of archived specimens. For a fixed number of participants, pooling designs incur little loss of estimation precision, and they can even improve precision by enabling inclusion of more participants with the same number of assays. A limitation that has discouraged the use of these methods in environmental epidemiology, however, is the lack of a valid way to adjust for creatinine (urinary dilution) when assaying a biomarker in urine or to adjust for serum lipids when assaying a lipophilic biomarker in serum. We aimed to develop practical strategies to accomplish those adjustments. METHODS:Our strategies either differentially dilute specimens before pooling equal aliquots or, alternatively, pool deliberately unequal aliquots from each specimen, where prior determinations of the adjustment factor in each individual specimen inform their differential dilution or unequal aliquot volumes. In addition, we show how to modify these strategies if, instead of just adjusting for creatinine per se, one needs to account for factors that influence creatinine. We carry out simulations under several causal scenarios. RESULTS:We demonstrate that the proposed strategies perform well in estimating the same adjusted association parameter as would be estimated by using individually-assayed specimens. CONCLUSION:By implementing the proposed strategies when forming specimen pools, one can greatly improve the efficiency of case-control studies that involve an expensive-to-assay exposure measured in biospecimens.

SUBMITTER: Weinberg CR

PROVIDER: S-EPMC6679734 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Adjustment for Urinary Creatinine or Serum Lipids for Analytes Assayed in Pooled Specimens.

Weinberg Clarice R CR Shi Min M O'Brien Katie M KM Umbach David M DM

Epidemiology (Cambridge, Mass.) 20190901 5

<h4>Background</h4>For case-control studies, pooling biologic specimens (cases with cases and controls with controls) can make it affordable to study a biomarker that is expensive to assay, while conserving quantities of archived specimens. For a fixed number of participants, pooling designs incur little loss of estimation precision, and they can even improve precision by enabling inclusion of more participants with the same number of assays. A limitation that has discouraged the use of these me ...[more]

PMID: 31205285

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Project description:Rationale & objectiveUrinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes.Study designObservational cohort.Setting & participantsWe analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m2 and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline.OutcomesThe primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation).Analytical approachWe used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration).ResultsDuring a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr.LimitationsCohort excluded patients with diabetes and overall had low levels of albuminuria.Conclusions1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.

Project description:BackgroundAcute kidney injury (AKI) is associated with high morbidity and mortality in dogs, but diagnosis may be impaired due the insensitivity of routine renal function biomarkers to detect earlier or milder forms of injury. Snake envenomation is one of several causes of AKI in dogs and humans. Dogs are commonly envenomated by the European adder (Vipera berus) between April and October each year, but few studies exist examining serial serum creatinine (sCr) and symmetric dimethylarginine (SDMA) measurements and AKI biomarkers in these dogs. Novel urinary biomarkers could improve clinical outcome by allowing earlier diagnosis of and intervention in AKI. The aim of this study was to assess the presence of AKI in dogs envenomated by V. berus at 12, 24 and 36 h after bite, as well as 14 days later, using sCr, SDMA and a panel of urinary AKI biomarkers normalised to urine creatinine (uCr), compared to a group of healthy control dogs.ResultsThirty-five envenomated dogs and 35 control dogs were included. Serum creatinine did not exceed the upper reference limit at any time point in any dog after envenomation. Serum SDMA did not exceed 0.89 μmol/L in any dog. Compared to controls, urinary albumin/uCr, neutrophil gelatinase-associated lipocalin/uCr and monocyte chemotactic protein-1/uCr were significantly elevated 12 h (P < 0.0001, P < 0.0001, P = 0.01), 24 h (P < 0.001, P < 0.001, P = 0.002) and 36 h (P < 0.001, P < 0.001, P = 0.0008) after bite. Osteopontin/uCr was higher 24 and 36 h after bite (P < 0.0001), kidney injury molecule-1/uCr, interleukin-8/uCr and γ- glutamyl transferase/uCr were significantly higher 36 h after bite (P = 0.003, P = 0.0005, P = 0.001). Urinary cystatin C/uCr was not significantly different to controls at any timepoint. Biomarker/uCr ratios were not significantly different 14 days after envenomation compared to controls.ConclusionUrinary biomarker/Cr ratios are indicative of mild transient, non-azotaemic AKI in dogs envenomated by V. berus.

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Adjustment for Urinary Creatinine or Serum Lipids for Analytes Assayed in Pooled Specimens.

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Adjustment for Urinary Creatinine or Serum Lipids for Analytes Assayed in Pooled Specimens.

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