Background-Well characterized genes affecting warfarin metabolism (CYP2C9) and sensitivity (VKORC1) explain one-third of the variability in therapeutic dose before the International Normalized Ratio (INR) is measured.

IMPORTANCE Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.OBJECTIVE To determine whether genotype-guided dosing improves the safety of warfarin initiation. DESIGN, SETTING, AND PATIENTSThe randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.INTERVENTIONS Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. MAIN OUTCOMES AND MEASURESThe primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. RESULTS Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.CONCLUSIONS AND RELEVANCE Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.

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Maternal substance abuse during pregnancy is a growing problem with major public health and legal concerns. In utero substance exposure may adversely affect neonatal development; pregnancy outcome; and the long-term behavioral, cognitive, and developmental abilities of the child. Also, serious legal implications are associated with substance abuse during pregnancy, including charges of child abuse and neglect that may result in the removal of the neonate from parental care and loss of custodial rights. Timely detection of in utero drug exposure is necessary for early identification and effective management of exposed newborns. Accurate identification of drug-exposed newborns relies on maternal history; clinical presentation of the newborn; and laboratory testing of biological maternal matrices (ie, urine, blood, oral fluid, sweat, hair, and breast milk), neonatal matrices (ie, urine, meconium, hair, and umbilical cord blood and tissue), and/or matrices from both the mother and neonate (ie, placenta and amniotic fluid). Evaluation of biological matrices can account for in utero exposure at various stages of gestation and approximate the period (recent versus chronic use) of substance exposure. Each matrix has its own unique advantages and limitations in terms of ease of collection, the window of gestational exposure represented, and sensitivity for different parent drug analytes and metabolites, which must be carefully considered for accurate interpretation of results. Analytical approaches to sample preparation and analysis vary based on the complexity of these biological matrices. Immunoassays are routinely used for screening, and chromatographic separation coupled to mass spectrometry detection method is commonly used for definitive (confirmatory) testing. Some laboratories use a single technology for all testing. This review provides a discussion on approaches used to detect drug-exposed newborns, biological specimens that have been studied to identify and characterize drug exposures, example analytical methods for meconium and umbilical cord tissue as well as considerations surrounding the interpretation of results. A possible algorithm for testing is also proposed.

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Copper is an essential element and, under conditions of overload, a toxicant. A dramatic example of copper toxicity is Wilson disease (WD), a treatable but often fatal condition that is difficult to diagnose and monitor. A method for direct measurement of free copper concentrations in serum or plasma ultrafiltrate by inductively coupled mass spectrometry was developed and validated to assist with diagnosis and monitoring WD. The method was shown to be accurate (94%-109% recoveries), linear (0.5-800 microg/dL [0.08-126 micromol/L]), and precise (coefficient of variation, < 15% over the analytic measurement range). A reference interval (0-10 microg/dL [0-1.6 micromol/L]) was determined parametrically with 137 healthy adult (20-59 years) blood donors. No statistically significant difference was observed in males (n = 69) vs females (n = 68). Free copper concentrations for patients diagnosed with WD were at least 6-fold greater than the upper limit of the reference interval before treatment but fell within the reference interval after treatment.

A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for simultaneous analysis of six major opiates in urine, serum, plasma, whole blood, and meconium is described. The six opiates included are codeine, morphine, hydrocodone, hydromorphone, oxycodone, and 6-acetylmorphine (6-AM). The method was compared to an in-house gas chromatography (GC)-MS method and an LC-MS-MS method performed by another laboratory. The sample preparation time was decreased by eliminating the glucuronide hydrolysis and derivatization required for GC-MS analysis, as well as by adapting the solid-phase extraction to elute directly into autosampler vials. These improvements illustrate the advantages of an LC-MS-MS method over a GC-MS method for opiates. The structural similarity of these six opiates and others in the opiate class causes a high potential for interference and false-positive results. Twelve opiate analogues and metabolites were evaluated for interference. The potential for interference was reduced by altering the MRM transitions chosen for the six opiates. The increased specificity of LC-MS-MS decreased the interference rate in urine to 3.9% compared to 13.6% on the in-house GC-MS method. The rate of positivity for 6-AM in meconium is described for the first time. In urine, 11.0% of morphine positive specimens were also positive for 6-AM compared to 8.3% in serum/plasma and 0.9% in meconium. Although 6-AM is infrequent in meconium, it provides a definitive proof of illegal heroin abuse by the pregnant mother. This method has been routinely used in our laboratory over the last 6 months on more than 1500 patient specimens.

Objective: To compare self-reported maternal marijuana use to quantitative biological sampling for a marijuana metabolite, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), in umbilical cord homogenate in a state with legalized marijuana. Methods: Cross-sectional study of women approached at time of admission for delivery with live, singleton pregnancies ≥ 24 weeks at two urban medical centers in Colorado. Maternal marijuana use was estimated by (1) report to health care provider on admission history and physical, (2) survey of self-reported use, and (3) liquid chromatography tandem mass spectrometry analysis of umbilical cord homogenate for THC-COOH. Women were categorized by survey-reported last use (≤30 days ago, 30 days to 1 year, more than 1 year, never), and proportion of women with cord results above the limit of detection and limit of quantification for THC-COOH was reported for each group. Comparisons between groups were made using contingency tables. Correlation between survey-reported frequency of use and quantitative THC-COOH cord homogenate results was evaluated. Results: We included 116 women with self-report surveys linked to cord assay results. Six percent (95% CI 2.5–12.0%) of participants reported use in the last 30 days on survey and 2.6% (95% CI 0.5–7.4%) of participants reported marijuana use to health care providers. On umbilical cord assay, 22.4% (95% CI 15.2–31.1%) had detectable THC-COOH. The proportion of women with detectable THC-COOH increased with more recent self-reported use. Survey-reported frequency of use in the past 30 days had moderate correlation with quantified umbilical cord THC-COOH (correlation coefficient 0.44, 95% CI 0.28–0.58, p<0.001). Conclusions: Umbilical cord sampling results in higher estimates of prenatal marijuana use than self-report even in the setting of legalization. Umbilical cord assays for THC-COOH demonstrate promise for quantifying use. Future studies should examine how the use of biological sampling informs the association between marijuana use and perinatal outcomes.