Publications by authors named "Kiang-Teck J Yeo"

49 Publications

Use of the angiogenic biomarker profile to risk stratify patients with fetal growth restriction.

Am J Obstet Gynecol MFM 2021 May 12:100394. Epub 2021 May 12.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States. Electronic address:

Background: Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exists in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers.

Objective: The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 (sFlt1) to placental growth factor (PlGF) ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a two-week time period.

Study Design: This was a prospective observational cohort study carried out in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks gestation were evaluated using serial two-week encounters from the time of enrollment until delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia labs and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for sFlt1 and PlGF after delivery in a double blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes.

Results: A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14, 33.57) weeks. Patients were divided into low risk (ratio < 38) and high risk (ratio ≥ 38) groups. Baseline characteristics of patients did not show any significant differences, including preeclampsia labs or ultrasound parameters, between the two groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when sFlt1/PlGF ≥ 38 (p = 0.02 and p = 0.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks of gestation, smaller neonatal birthweight, and a smaller time to delivery from testing to delivery.

Conclusions: Among patients with fetal growth restriction, the sFlt1/PlGF ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100394DOI Listing
May 2021

Longitudinal SARS-CoV-2 antibody study using the Easy Check COVID-19 IgM/IgG™ lateral flow assay.

PLoS One 2021 4;16(3):e0247797. Epub 2021 Mar 4.

Truvian Sciences, San Diego, California, United States of America.

Since the initial identification of the novel coronavirus SARS-CoV-2 in December of 2019, researchers have raced to understand its pathogenesis and begun devising vaccine and treatment strategies. An accurate understanding of the body's temporal immune response against SARS-CoV-2 is paramount to successful vaccine development and disease progression monitoring. To provide insight into the antibody response against SARS-CoV-2, plasma samples from 181 PCR-confirmed COVID-19 patients collected at various timepoints post-symptom onset (PSO) were tested for the presence of anti-SARS-CoV-2 IgM and IgG antibodies via lateral flow. Additionally, 21 donors were tracked over time to elucidate patient-specific immune responses. We found sustained levels of anti-SARS-CoV-2 antibodies past 130 days PSO, with 99% positivity observed at 31-60 days PSO. By 61-90 days PSO, the percentage of IgM-/IgG+ results were nearly equal to that of IgM+/IgG+ results, demonstrating a shift in the immune response with a decrease in IgM antibody levels. Results from this study not only provide evidence that the antibody response to COVID-19 can persist for over 4 months, but also demonstrates the ability of Easy Check™ to monitor seroconversion and antibody response of patients. Easy Check was sufficiently sensitive to detect antibodies in patient samples as early as 1-4 days PSO with 86% positivity observed at 5-7 days PSO. Further studies are required to determine the longevity and efficacy of anti-SARS-CoV-2 antibodies, and whether they are protective against re-infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932143PMC
March 2021

Implementation of pharmacogenomic testing in oncology care (PhOCus): study protocol of a pragmatic, randomized clinical trial.

Ther Adv Med Oncol 2020 17;12:1758835920974118. Epub 2020 Dec 17.

Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center and Biological Sciences, Chicago, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA.

Background: Many cancer patients who receive chemotherapy experience adverse drug effects. Pharmacogenomics (PGx) has promise to personalize chemotherapy drug dosing to maximize efficacy and safety. Fluoropyrimidines and irinotecan have well-known germline PGx associations. At our institution, we have delivered PGx clinical decision support (CDS) based on preemptively obtained genotyping results for a large number of non-oncology medications since 2012, but have not previously evaluated the utility of this strategy for patients initiating anti-cancer regimens. We hypothesize that providing oncologists with preemptive germline PGx information along with CDS will enable individualized dosing decisions and result in improved patient outcomes.

Methods: Patients with oncologic malignancies for whom fluoropyrimidine and/or irinotecan-inclusive therapy is being planned will be enrolled and randomly assigned to PGx and control arms. Patients will be genotyped in a clinical laboratory across panels that include actionable variants in and . For PGx arm patients, treating providers will be given access to the patient-specific PGx results with CDS prior to treatment initiation. In the control arm, genotyping will be deferred, and dosing will occur as per usual care. Co-primary endpoints are dose intensity deviation rate (the proportion of patients receiving dose modifications during the first treatment cycle), and grade ⩾3 treatment-related toxicities throughout the treatment course. Additional study endpoints will include cumulative drug dose intensity, progression-free survival, dosing of additional PGx supportive medications, and patient-reported quality of life and understanding of PGx.

Discussion: Providing a platform of integrated germline PGx information may promote personalized chemotherapy dosing decisions and establish a new model of care to optimize oncology treatment planning.
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http://dx.doi.org/10.1177/1758835920974118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750903PMC
December 2020

Is Adding IgM Antibody to Polymerase Chain Reaction Testing Useful for COVID-19 Travel Screening?

Am J Clin Pathol 2021 02;155(3):321-323

Department of Pathology, University of Chicago, Chicago, IL.

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http://dx.doi.org/10.1093/ajcp/aqaa270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929450PMC
February 2021

Evaluation of the Truvian Easy Check COVID-19 IgM/IgG Lateral Flow Device for Rapid Anti-SARS-CoV-2 Antibody Detection.

Am J Clin Pathol 2021 02;155(2):286-295

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: To evaluate the analytical and clinical performance of the Truvian Easy Check coronavirus disease 2019 (COVID-19) IgM/IgG anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody test.Serologic assays have become increasingly available for surveillance through the Food and Drug Administration emergency use authorization in the ongoing COVID-19 global pandemic. However, widespread application of serologic assays has been curbed by reports of faulty or inaccurate tests. Therefore, rapid COVID-19 antibody tests need to be thoroughly validated prior to their implementation.

Methods: The Easy Check device was analytically evaluated and its performance was compared with the Roche Elecsys anti-SARS-CoV-2 antibody assay. The test was further characterized for cross-reactivity using sera obtained from patients infected by other viruses. Clinical performance was analyzed with polymerase chain reaction-confirmed samples and a 2015 prepandemic reference sample set.

Results: The Easy Check device showed excellent analytical performance and compares well with the Roche Elecsys antibody assay, with an overall concordance of 98.6%. Clinical performance showed a sensitivity of 96.6%, a specificity of 98.2%, and an overall accuracy of 98.1%.

Conclusions: The Easy Check device is a simple, reliable, and rapid test for detection of SARS-CoV-2 seropositivity, and its performance compares favorably against the automated Roche Elecsys antibody assay.
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http://dx.doi.org/10.1093/ajcp/aqaa221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665287PMC
February 2021

Analytical and Clinical Evaluation of the Automated Elecsys Anti-SARS-CoV-2 Antibody Assay on the Roche cobas e602 Analyzer.

Am J Clin Pathol 2020 10;154(5):620-626

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: To evaluate the analytical and clinical performance of the automated Elecsys anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody (Elecsys Ab) assay on the Roche cobas e602 analyzer. With the ongoing global coronavirus disease 2019 (COVID-19) pandemic, widespread and routine serologic testing of SARS-CoV-2 remains a pressing need. To better understand its epidemiologic spread and to support policies aimed at curtailing further infections, reliable serologic testing is crucial for providing insight into the dynamics of the spread of COVID-19 on a population level.

Methods: The presence of anti-SARS-CoV-2 antibodies in polymerase chain reaction-positive, confirmed COVID-19 patient samples was determined using the Elecsys Ab assay on the Roche cobas e602 analyzer. The precision and cross-reactivity of the Elecsys Ab assay were characterized and its performance was compared against the EuroImmun IgA/IgG antibody (EuroImmun Ab) assay. Calculated sensitivity, specificity, and positive and negative predictive values were assessed.

Results: The Elecsys Ab assay demonstrated good precision, had no cross-reactivity with other viral samples, and showed 100% concordance with the EuroImmun Ab assay. Excellent clinical performance with respect to sensitivity, specificity, and positive and negative predictive values was observed.

Conclusions: The Elecsys Ab assay is a precise and highly reliable automated platform for clinical detection of seropositivity in SARS-CoV-2 infection.
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http://dx.doi.org/10.1093/ajcp/aqaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454296PMC
October 2020

Evaluation of interference effects from hemolysis, icterus and lipemia on the Roche Elecsys® Anti-SARS-CoV-2 assay.

Clin Chim Acta 2020 Oct 26;509:293-294. Epub 2020 Jun 26.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States. Electronic address:

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http://dx.doi.org/10.1016/j.cca.2020.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318977PMC
October 2020

False-Positive Hepatitis B Surface Antibody Results: An Example of Reagent Carryover.

J Appl Lab Med 2020 03;5(2):429-431

Department of Pathology, Pritzker School of Medicine, University of Chicago, Chicago, IL.

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http://dx.doi.org/10.1093/jalm/jfz015DOI Listing
March 2020

Pharmacogenomic-Based Decision Support to Predict Adherence to Medications.

Clin Pharmacol Ther 2020 08 25;108(2):368-376. Epub 2020 May 25.

The University of Chicago Center for Personalized Therapeutics, Chicago, Illinois, USA.

Poor adherence is associated with worse disease outcomes. Pharmacogenomics provides a possible intervention to address adherence. We hypothesized that pharmacogenomic-informed care could increase adherence. Patients in a prospective case-control study underwent preemptive pharmacogenomic genotyping with results available for provider use at the point of care; controls (not genotyped) were treated by the same providers. Over 6,000 e-prescriptions for 39 medications with actionable pharmacogenomic information were analyzed. Composite adherence, measured by modified proportion of days covered (mPDC), was compared between cases/controls and genomically concordant vs. genomically higher-risk medications. Overall, 536 patients were included. No difference in mean mPDC was observed due to availability of pharmacogenomic guidance. However, case patients prescribed high-risk pharmacogenomic medications were more than twice as likely to have low mPDC for these medications compared with genomically concordant prescriptions (odds ratio = 2.4 (1.03-5.74), P < 0.05). This study is the first to show that composite pharmacogenomic information predicts adherence.
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http://dx.doi.org/10.1002/cpt.1838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363565PMC
August 2020

Analytical Differences in Intraoperative Parathyroid Hormone Assays.

J Appl Lab Med 2019 03 1;3(5):788-798. Epub 2019 Feb 1.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL.

Background: We compared the rates of intraoperative parathyroid hormone (PTH) decline using the Siemens Immulite Turbo PTH and Roche Elecsys short turnaround time PTH assays in 95 consecutive surgical patients to investigate analytical and turnaround time (TAT) differences between the tests performed in the operating room (OR) vs the central clinical chemistry laboratory (CCL).

Methods: Serial blood samples from 95 patients undergoing parathyroidectomy were collected and measured using the 2 immunoassays. Specimens from the first 15 patients were measured simultaneously in the OR and CCL and used for the TAT study. In addition to 2 baseline samples, specimens were collected at 5, 10, and 15 min (for some patients, >15 min) after parathyroidectomy.

Results: In the TAT study, a significant difference was observed (OR median 20 min vs CCL median 27 min; < 0.05). Of the 95 patient series, slower rates of parathyroid hormone decrease were observed in approximately 20% of the patients when comparing the Roche with the Immulite immunoassay.

Conclusions: There was a slightly longer TAT in the CCL compared with running the assay directly within the OR (median difference of approximately 7 min). For a majority of the patients, both methods showed equivalent rates of PTH decline; however, for approximately 20% of the patients, there was a slower rate of PTH decline using the Roche assay.
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http://dx.doi.org/10.1373/jalm.2018.026815DOI Listing
March 2019

Evaluation of a New Generation Automated Assay for 25-Hydroxy Vitamin D Based on Competitive Protein Binding.

J Appl Lab Med 2019 09 26;4(2):247-253. Epub 2019 Jun 26.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL;

Background: The interest for vitamin D has exponentially increased testing demand for 25-hydroxy vitamin D [25(OH)D]. Consequently, many laboratories are switching from LC-MS/MS methods to automated, high-throughput immunoassays. One of the major potential issues with these assays has been the lack of cross-reactivity with 25(OH)D2.

Methods: We have evaluated the Roche Elecsys vitamin D total II assay for accuracy by comparing 79 patient samples with LC-MS/MS. The cross-reactivity for 25(OH)D2 was evaluated by analyzing samples with high 25(OH)D2 separately and estimating 25(OH)D2 recovery, as well as by spiking of 25(OH)D2. The assay was further evaluated for precision, linearity, sample type, and common interferences.

Results: There was mostly good agreement between the Elecsys and LC-MS/MS assays (Deming regression: = 0.95 + 0.70), with an overall bias of 2.3% (-0.84 ng/mL). However, there were 6 out of 79 (7.6%) discordant samples. The Deming regression for samples with high 25(OH)D2 compared to LC-MS/MS showed similar slope and intercept ( = 0.97 - 1.1). The average recovery of 25(OH)D2 for these samples was 90%. The initial precision studies were in general agreement with the package insert, but long-term clinical use showed higher-than-claimed imprecision (11.7%-14.4% at 12 ng/mL and 6.9%-7.6% at 27 ng/mL; claimed: 7.2% and 5.0%, respectively). We observed 1 falsely high result in plasma, an issue previously addressed by Roche in a medical device correction.

Conclusions: The analytical performance of the Roche Vitamin D assay was acceptable, and the assay had a good cross-reactivity for 25(OH)D2.
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http://dx.doi.org/10.1373/jalm.2018.028415DOI Listing
September 2019

Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation.

Pharmacogenomics J 2020 02 11;20(1):126-135. Epub 2019 Sep 11.

University of Chicago, Center for Personalized Therapeutics, Chicago, IL, USA.

The importance of genetic ancestry characterization is increasing in genomic implementation efforts, and clinical pharmacogenomic guidelines are being published that include population-specific recommendations. Our aim was to test the ability of focused clinical pharmacogenomic SNP panels to estimate individual genetic ancestry (IGA) and implement population-specific pharmacogenomic clinical decision-support (CDS) tools. Principle components and STRUCTURE were utilized to assess differences in genetic composition and estimate IGA among 1572 individuals from 1000 Genomes, two independent cohorts of Caucasians and African Americans (AAs), plus a real-world validation population of patients undergoing pharmacogenomic genotyping. We found that clinical pharmacogenomic SNP panels accurately estimate IGA compared to genome-wide genotyping and identify AAs with ≥70 African ancestry (sensitivity >82%, specificity >80%, PPV >95%, NPV >47%). We also validated a new AA-specific warfarin dosing algorithm for patients with ≥70% African ancestry and implemented it at our institution as a novel CDS tool. Consideration of IGA to develop an institutional CDS tool was accomplished to enable population-specific pharmacogenomic guidance at the point-of-care. These capabilities were immediately applied for guidance of warfarin dosing in AAs versus Caucasians, but also provide a real-world model that can be extended to other populations and drugs as actionable genomic evidence accumulates.
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http://dx.doi.org/10.1038/s41397-019-0095-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184888PMC
February 2020

Development of a Nonradioactive Platelet Serotonin Uptake and Release Assay by Micro-Liquid Chromatography Tandem Mass Spectrometry Using Minimal Blood Volume.

Am J Clin Pathol 2019 11;152(6):718-724

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: Analysis of platelet functional responses to stimuli is presently quite limited with respect to measurement of dense granule secretion. We sought to develop a nonradioactive assay of stimulated serotonin release using liquid chromatography tandem mass spectrometry (LC-MS/MS).

Methods: Citrated whole blood (200 μL) was incubated with deuterated serotonin (d45-HT). Following uptake by platelets, blood was diluted 10-fold and aliquots were incubated with platelet stimuli. Following stimulation, blood was further diluted, centrifuged, and supernatant was assayed for released d45-HT by micro-LC-MS/MS.

Results: This study demonstrated a broad linear range of 50 to 2,000 pg/mL d45-HT, with a total precision of less than 15.0% coefficient of variation at all quality control levels and a limit of quantitation of 50 pg/mL.

Conclusions: Quantification of d45-HT by micro-LC-MS/MS assay offers a highly sensitive, nonradioactive methodology for quantitating platelet serotonin uptake and dense granule secretion, requiring only small volumes of patient blood.
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http://dx.doi.org/10.1093/ajcp/aqz094DOI Listing
November 2019

Angiogenic Factor Estimation as a Warning Sign of Preeclampsia-Related Peripartum Morbidity Among Hospitalized Patients.

Hypertension 2019 04;73(4):868-877

From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (J.L.P., S.C., A.M., R.M., H.R., R.N., H.N., D.Y., S.S., S.R.), University of Chicago, IL.

Preeclampsia-related morbidity and mortality is rising predominantly because of delayed identification of patients at risk for preeclampsia with severe features and associated complications. This study explored the association between angiogenic markers (sFlt1 [soluble fms-like tyrosine kinase-1]) and PlGF [placental growth factor]) and preeclampsia-related peripartum complications. Normotensive women or those with hypertensive disorders of pregnancy were enrolled. Blood samples were collected within 96 hours before delivery, and angiogenic markers were measured on an automated platform. Our study included 681 women, 375 of which had hypertensive disorders. Of these, 127 (33.9%) had severe preeclampsia, and 71.4% were black. Compared with normotensive women, women with severe preeclampsia had higher levels of sFlt1 (9372.5 versus 2857.0 pg/mL; P<0.0001), lower PlGF (51.0 versus 212.0 pg/mL; P<0.0001), and a high sFlt1/PlGF (212.0 versus 14.0; all P<0.0001). A similar trend in sFlt1, PlGF, and sFlt1/PlGF was found in those women with complications secondary to preeclampsia (all P<0.001). The highest tertile of sFlt1/PlGF was strongly associated with severe preeclampsia in a multivariable analysis. Among patients with a hypertensive disorder of pregnancy, 340 (90.7%) developed postpartum hypertension, of which 50.4% had mild, and 40.3% had severe postpartum hypertension. The sFlt1/PlGF ratio was significantly higher for severe and mild postpartum hypertension compared with women with normal postpartum blood pressures (73.5, 46.0, and 13.0, respectively; P values<0.0001). Furthermore, the highest tertile of antepartum sFlt1/PlGF was associated with postpartum hypertension ( P=0.004). This study demonstrates a significant association between an abnormal angiogenic profile before delivery and severe preeclampsia and peripartum complications.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12205DOI Listing
April 2019

Association of antepartum blood pressure levels and angiogenic profile among women with chronic hypertension.

Pregnancy Hypertens 2018 Oct 5;14:110-114. Epub 2018 Sep 5.

Section of Maternal Fetal Medicine/Department of Obstetrics & Gynecology, University of Chicago, Chicago, IL, USA. Electronic address:

Background: Angiogenic factors have been implicated in the pathogenesis of preeclampsia. This pilot study explored the association between antenatal blood pressure levels and angiogenic biomarkers (sFlt1 and PlGF) among women with chronic hypertension (cHTN).

Methods: Blood samples were collected from women with cHTN (with/without superimposed preeclampsia) within 96 h prior to delivery. Subjects were stratified by mean outpatient BP as controlled (cBP < 140/90) or uncontrolled (uBP ≥ 140/90). Descriptive statistics were generated and assessed as appropriate. Logistic regression was employed to assess for adverse pregnancy outcomes between groups.

Results: Data from seventy-eight women were analyzed, of which 58 (74.4%) were African American. Fifty-six (71.8%) had cBP and 22 (28.2%) had uBP. Use of antepartum outpatient antihypertensive medications was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01). Compared to women with cBP, women with uBP had higher levels of pre-delivery sFlt1 and sFlt1/PlGF ratio (sFlt: 4218.5 vs. 3056.0 pg/ml, p = 0.046; sFlt/PlGF: 62.5 vs. 25.0, p = 0.04). Additionally, more uBP patients had superimposed preeclampsia with severe features (54.6% vs. 25.0%; p = 0.01) and preterm delivery (defined as a gestational age <35 weeks (40.9% vs. 10.7%; p = 0.002)) than cBP patients. In the multivariable model, women with uBP had greater odds of preterm delivery (OR 6.78; p = 0.01), superimposed preeclampsia (OR 3.20; p = 0.03) and preeclampsia with severe features (OR 3.27; p = 0.04) than women with cBP.

Conclusion: In women with cHTN, elevated antepartum BP is associated with worsened outcomes and may be associated with abnormal angiogenic profile at delivery. Larger studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.preghy.2018.09.003DOI Listing
October 2018

Reengineering Critical Laboratory Testing for Timely Chemotherapeutic Management.

J Appl Lab Med 2018 Sep;3(2):240-249

Department of Pathology, The University of Chicago, Chicago, IL.

Background: Delivery of cytotoxic therapy is a complex multifaceted process that involves harmonized collaboration between all systems involved. Optimizing laboratory turnaround time (TAT) ensures timely delivery of chemotherapy, which potentially translates into improved patient outcomes and satisfaction. In this study, we aimed to reduce the laboratory TAT for key laboratory tests to optimize the timely administration of chemotherapy.

Methods: TAT data for complete blood count (CBC) and comprehensive metabolic panel (CMP) included specimen collection to receipt (Col-Rcv), specimen receipt to result release (Rcv-Res), and the overall TAT from specimen collection to result release (Col-Res). Work flows were reconfigured to transport CBC specimens directly to the hematology laboratory after collection and to treat all CMP samples from chemotherapy clinics as urgent [i.e., shortest turnaround time (STAT)]. From the CMP, total bilirubin and creatinine-the 2 key analytes for liver and renal toxicity assessment before chemotherapy drug administration-were analyzed on ABL 800 whole blood analyzers to further improve the laboratory TAT.

Results: CBC showed a significant reduction in the median (Col-Res) TAT to 16 min (P < 0.0001). For CMP, by processing all specimens as STAT samples, the median (Col-Res) TAT was reduced from 74 min to 54 min (P < 0.0001), and it was further reduced to 9 min (P < 0.0001) for total bilirubin and creatinine.

Conclusion: Careful work flow analysis and reengineering of preanalytical and analytical process for key laboratory tests significantly reduced median overall TAT to <20 min, which helped facilitate more timely delivery of chemotherapy, without necessitating the construction of a satellite laboratory.
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http://dx.doi.org/10.1373/jalm.2017.025973DOI Listing
September 2018

Development and validation of a targeted affinity-enrichment and LC-MS/MS proteomics approach for the therapeutic monitoring of adalimumab.

Clin Chim Acta 2018 Aug 9;483:308-314. Epub 2018 May 9.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States.

Background: The anti-tumor necrosis factor alpha (TNFα) therapeutic monoclonal antibodies (mAbs), such as adalimumab, are widely used in the treatment of rheumatoid arthritis, inflammatory bowel diseases, and other auto-immune diseases. The administration of adalimumab can elicit the immune responses from some patients, resulting in the formation of anti-drug antibodies (ADAbs). The ADAbs can diminish the therapeutic effects of adalimumab by neutralizing the TNFα binding site or increasing its clearance from circulation.

Methods: To effectively monitor the therapeutic concentrations of adalimumab, we developed and validated a targeted quantitative proteomic assay to determine the circulating concentrations of adalimumab. Since drug effects can be attenuated by ADAbs, the method adopted an affinity-enrichment step to selectively quantify the bioavailable forms of adalimumab in patient serum samples.

Results: The performance of the LC-MS/MS based assay provides the analytical measuring range and precisions applicable for the therapeutic monitoring of adalimumab. It also provides comparable results to a cell-based activity assay when evaluating patient samples with different concentrations of adalimumab.

Conclusion: Our assay can quantify both sub-therapeutic and therapeutic concentrations of bioavailable adalimumab in patient serum samples. This assay design provides an alternative to isotope-labeled peptides approach currently adopted in targeted proteomics methods.
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http://dx.doi.org/10.1016/j.cca.2018.05.015DOI Listing
August 2018

Losing sight of the Forest for the trees: Why clinical laboratories need to perform their own interference studies.

Clin Chim Acta 2018 08 8;483:239-240. Epub 2018 May 8.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 0004, TW010, Chicago, IL 60637, United States. Electronic address:

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http://dx.doi.org/10.1016/j.cca.2018.05.008DOI Listing
August 2018

Analytical validation of soluble fms-like tyrosine and placental growth factor assays on B·R·A·H·M·S KRYPTOR Compact Plus automated immunoassay platform.

Pregnancy Hypertens 2018 Jan 2;11:66-70. Epub 2018 Jan 2.

Department of Pathology, The University of Chicago, Chicago, IL, United States. Electronic address:

Background: Preeclampsia is one of the leading hypertensive disorders of pregnancy. Angiogenic biomarkers such as anti-angiogenic factor soluble fms-like tyrosine kinase 1 (sFlt1) and pro-angiogenic factor placental growth factor (PlGF) are involved in the pathophysiology of preeclampsia.

Objective: The aim of this study is to validate the analytical performance of sFlt1 and PlGF on the B·R·A·H·M·S KRYPTOR Compact Plus (ThermoFisher Scientific).

Study Design: We examined K-EDTA plasma samples from 50 patients on B·R·A·H·M·S KRYPTOR Compact Plus, an automated immunoassay platform. QC materials were used to assess intra- and inter-precision of the assay. Lower limit of quantitation and interference studies were determined using pooled patient plasma.

Results: The sFlt1 and PlGF assays demonstrated an analytical measuring range of 90-69,000 pg/mL and 11-7000 pg/mL, respectively (r > 0.99). Lower limit of quantitation (20% CV) was interpolated to be 35 pg/mL for sFlt1 and 10 pg/mL for PlGF. Total precision for both assay displayed CVs of <10%. Interference studies showed that both assays were not significantly affected by hemolysis up to an H-index of 1100 for sFlt1 and 300 for PlGF; L- and I-index of 800 and 80 respectively for both assays. The Passing-Bablok regression analysis for sFlt1/PlGF yielded an equation of y = 1.05x + 0.02, and the Bland Altman analysis showed an average bias of 0.84.

Conclusion: Plasma levels of sFlt1 and PlGF measured on the B·R·A·H·M·S KRYPTOR Compact Plus platform demonstrate excellent analytical performance and are acceptable as clinical grade assays.
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http://dx.doi.org/10.1016/j.preghy.2017.12.009DOI Listing
January 2018

Smith-Lemli-Opitz Syndrome in a newborn infant with developmental abnormalities and low endogenous cholesterol.

Clin Chim Acta 2018 Apr 31;479:208-211. Epub 2018 Jan 31.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, United States.

Background: Patients with Smith-Lemli-Opitz Syndrome (SLOS) have defective endogenous cholesterol synthesis, and present with decreased cholesterol levels and multiple developmental dysmorphologies.

Case Description: A newborn infant with normal XY karyotype and normal microarray was born with multiple developmental defects and ambiguous genitalia. The patient was diagnosed with SLOS, following biochemical genetic analysis of serum 7-DHC concentrations. The clinical course of the patient was further complicated by the comorbidities associated with SLOS and the bacterial infections.

Conclusion: We provide a detailed biochemical profile of the SLOS patient. The report can help us further understand the pathological impacts of cholesterol synthesis deficiency and provide relevant clinical management with outcome of this rare genetic disorder.
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http://dx.doi.org/10.1016/j.cca.2018.01.027DOI Listing
April 2018

Wellness Initiatives: Benefits and Limitations.

Clin Chem 2017 06 21;63(6):1063-1068. Epub 2017 Apr 21.

Associate Professor of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY.

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http://dx.doi.org/10.1373/clinchem.2017.273672DOI Listing
June 2017

Validation of an Extensive CYP2D6 Assay Panel Based on Invader and TaqMan Copy Number Assays.

J Appl Lab Med 2017 Mar;1(5):471-482

Department of Pathology, UChicago Advanced Technology Clinical Laboratory, The University of Chicago, Chicago, IL.

Background: CYP2D6 is involved in the oxidative metabolism of approximately 20% of all clinically used medications. Genotyping cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), is a challenge because of the high complexity of the locus.

Methods: Twenty-nine CYP2D6 sequence variants were genotyped in 50 deidentified patient samples and 29 Coriell DNAs by Invader assay, and results were compared with Infiniti assay and Sanger sequencing. To determine CYP2D6 copy number, 3 TaqMan real-time hydrolysis probes were used and results were compared with long-range PCR. Discrimination of the duplicated alleles was done on 17 DNA samples with 3 copies of CYP2D6 by long-range PCR followed by Invader genotyping and single nucleotide extension for the comparison.

Results: Complete concordance was observed for all samples between platforms except for 2 samples due to the lack of the *45 allele in the Infiniti panel. Reproducibility with the Invader assay and TaqMan copy number was 100%. Analytical sensitivity using DNA with 2 copies was determined to be 10 ng DNA for the Invader assay and 1 ng/μL DNA for the TaqMan assay, respectively. Complete concordance and reproducibility were observed for duplicated allele discrimination with the exception of 1 sample, determined to be *29/*43X2 by the Invader test and *1X2/*29 by the Infiniti method, which did not test for *43.

Conclusions: This validation study showed that Invader and TaqMan assay combined panel provides an attractive, valid, highly accurate, and reproducible approach for CYP2D6 genotyping for clinical implementation.
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http://dx.doi.org/10.1373/jalm.2016.021923DOI Listing
March 2017

High-Sensitivity Micro LC-MS/MS Assay for Serum Estradiol without Derivatization.

J Appl Lab Med 2016 Jul;1(1):14-24

Department of Pathology, The University of Chicago, Chicago, IL.

Background: There are considerable demands to accurately measure estradiol (E2) at low concentrations (<20 pg/mL) in postmenopausal women, men, pediatric patients, and patients receiving breast cancer treatment. Most current high-sensitivity LC-MS/MS E2 methods require large sample volumes and involve complex sample preparations with dansyl chloride derivatization. Our study aims to develop a high-sensitivity, underivatized method using micro LC-MS/MS to reliably measure E2 concentrations below 5 pg/mL by the use of low sample volume.

Methods: A total of 290 μL of sample was mixed with internal standard (IS), E2-d4, and extracted with a mixture of hexane/ethyl acetate (90/10) (v/v). After extraction, sample was separated by Eksigent Ekspert™ micro LC 200 system with a flow rate of 35 μL/min in a total run time of 3.5 min and detected by SCIEX QTRAP 6500 mass spectrometer in a negative mode using transitions: 271/145 (quantifier) and 271/143 (qualifier). In this method, it was crucial to use HPLC columns with stability at a pH >10.

Results: The validation study demonstrated broad linear ranges (3.0-820.0 pg/mL) with r2 > 0.999. Total precision was below 15% at all QC levels, and limit of quantification (LOQ) was 3.0 pg/mL. Our method showed good correlation with E2 RIA (r2 = 0.96, bias = -1.0 pg/mL) and modest correlation with E2 Roche Cobas automated immunoassay (r2 = 0.86, bias = 6.0 pg/mL).

Conclusions: In conclusion, we developed and validated a routinely applicable micro LC-MS/MS method without derivatization for E2 in blood samples with an LOQ of 3.0 pg/mL.
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http://dx.doi.org/10.1373/jalm.2016.020362DOI Listing
July 2016

Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response.

Int Immunopharmacol 2015 Aug 21;27(2):249-56. Epub 2015 May 21.

Department of Pathology, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA. Electronic address:

To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (p<0.05), and 24hour free testosterone AUC was significantly raised from a mean of 35.0pg-hr/mL to 53.89pg-hr/mL. Assessment of the typical symptoms of fibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved.
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http://dx.doi.org/10.1016/j.intimp.2015.05.016DOI Listing
August 2015

Discrepant serum and urine β-hCG results due to production of β-hCG by a cribriform-morular variant of thyroid papillary carcinoma.

Clin Chim Acta 2015 Jan 30;438:181-5. Epub 2014 Aug 30.

Department of Pathology, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States. Electronic address:

Background: Although patients with medullary thyroid cancer are known to present with paraneoplastic hormone production, this is much less common with papillary thyroid cancer.

Methods: We present a patient with the cribriform morular variant of papillary thyroid cancer in association with familial adenomatous polyposis who developed a positive pregnancy test in the absence of known pregnancy. The patient had developed vaginal bleeding, and her laboratory testing was characterized by elevated serum human chorionic gonadotropin (β-hCG) concentrations, but negative qualitative urine results. After a thorough gynecological evaluation to exclude unexpected normal, ectopic, or molar pregnancy, we pursued an evaluation for other sources of β-hCG production.

Results: We showed that the elevated serum β-hCG concentrations were not the result of heterophile antibody interferences, and ultimately we proved that her recurrent tumor produced the ectopic β-hCG. This is the first report of β-hCG production by papillary thyroid cancer. Thus, the possibility of ectopic production of β-hCG by papillary thyroid cancer needs to be included in the differential diagnosis of elevated hCG concentration in the absence of pregnancy.

Conclusions: This study of an unusual paraneoplastic syndrome highlights the importance of investigating discrepancies in the clinical laboratory.
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http://dx.doi.org/10.1016/j.cca.2014.08.026DOI Listing
January 2015

Clinical evaluation of the QMS® Tacrolimus immunoassay.

Clin Chim Acta 2014 Apr 8;431:270-5. Epub 2014 Feb 8.

Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States.

Background: Tacrolimus, a widely used immunosuppressant, inhibits T-lymphocyte signal transduction and cytokine upregulation. We evaluated and compared the performance of a newly developed tacrolimus immunoassay method to LC-MS/MS.

Method: Analytical performance was assessed using quality control materials and whole blood patient samples. Interferences studies were performed using pooled whole-blood samples spiked with each interferent, respectively. Comparison studies were conducted using 145 de-identified whole blood samples collected after routine tacrolimus analysis by LC-MS/MS.

Results: CVs were between 3.9 and 8.1% and the method was linear (r(2)=0.99) up to 30.0 ng/ml. Calibration was stable ≤12 days and LOQ was 0.7 ng/ml (14.4% CV). Bilirubin (≤48 mg/dl), hemoglobin (≤345 mg/dl), and triglycerides (<2800 mg/dl) showed no significant interference. Comparison (Passing-Bablok regression) for all samples showed a proportional bias of 17%. Comparisons of liver and kidney transplant patients showed slope biases of 22% and 31%, respectively, whereas other remaining transplant patients (stem cell, heart, lung, and islet) showed a slope bias of 0.98.

Conclusions: Overall, the QMS Tacrolimus Immunoassay showed good analytical performance. Comparison studies showed a proportional bias of 17%, which can be attributed to the significant number of liver and kidney transplant patients present in this study (121/145).
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http://dx.doi.org/10.1016/j.cca.2014.01.027DOI Listing
April 2014

Reducing the risk of hyperammonemia from transfusion of stored red blood cells.

Transfus Apher Sci 2013 Dec 29;49(3):459-62. Epub 2013 May 29.

Department of Pathology, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.

Ammonia concentration increases in red cell units (RBCs) during storage. We measured absolute amounts of ammonia (AA) per unit serially in stored RBCs and before and after removal of the supernatant by volume reduction (VR) or washing. Ammonia increased 6.4-fold in untreated units over 31 days. VR decreased AA 3.7-fold, whereas washing decreased it 38-fold (p<0.0001). At least for certain patients, e.g., infants receiving large volume transfusions and patients in liver failure, it may be advisable to use RBCs as fresh as possible and to limit infusion (by VR or washing) of ammonia in the supernatant.
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http://dx.doi.org/10.1016/j.transci.2013.05.002DOI Listing
December 2013