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Supplementary Figure S1; Supplementary Table S1.

Purpose: Fecal occult blood testing is recommended as first-line screening to detect colorectal cancer (CRC). We evaluated markers and marker combinations in serum as an alternative to improve the detection of CRC.Experimental Design: Using penalized logistic regression, 6 markers were selected for evaluation in 1,027 samples (301 CRC patients, 143 patients with adenoma, 266 controls, 141 disease controls, and 176 patients with other cancer). The diagnostic performance of each marker and of marker combinations was assessed.Results: To detect CRC from serum samples, we tested 22 biomarkers. Six markers were selected for a marker combination, including the known tumor markers CEA (carcinoembryonic antigen) and CYFRA 21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin (OPN), anti-p53, and seprase. CEA showed the best sensitivity at 95% specificity with 43.9%, followed by seprase (42.4%), CYFRA 21-1 (35.5%), OPN (30.2%), ferritin (23.9%), and anti-p53 (20.0%). A combination of these markers gave 69.6% sensitivity at 95% specificity and 58.7% at 98% specificity. Focusing on International Union against Cancer (UICC) stages 0–III reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a subcollective, with matched stool samples (75 CRC cases and 234 controls), the sensitivity of the marker combination was comparable with fecal immunochemical testing (FIT) with 82.4% and 68.9% versus 81.8% and 72.7% at 95% and 98% specificity, respectively.Conclusions: The performance of the serum marker combination is comparable with FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis. Clin Cancer Res; 16(24); 6111–21. ©2010 AACR.

Background For pregnant women with suspected preeclampsia, the soluble fms-like tyrosine-kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is a biomarker to aid diagnosis. We performed method comparisons between Elecsys® and Kryptor sFlt-1 and PlGF immunoassays and assessed the diagnostic performance for preeclampsia. Methods Serum samples from a case-control study involving 113 pregnant women with preeclampsia/elevated liver enzymes and low platelet count (HELLP) and 270 controls were analyzed. sFlt-1 and PlGF were measured using Roche Elecsys® and BRAHMS Kryptor sFlt-1/PlGF immunoassays. The sFlt-1/PlGF ratios were calculated, and Passing-Bablok regression/Bland-Altman plots were performed. Gestation-specific cut-offs, ≤33 and ≥85/≥110, were assessed. Results Mean (±2 standard deviation [SD]) differences between the Elecsys® and Kryptor values were: sFlt-1, 173.13 pg/mL (6237.66, −5891.40); PlGF, −102.71 pg/mL (186.06, −391.48); and sFlt-1/PlGF, 151.74 (1085.11, −781.63). The Elecsys® and Kryptor immunoassays showed high correlation: Pearson’s correlation coefficients were 0.913 (sFlt-1) and 0.945 (PlGF). Slopes were 1.06 (sFlt-1) and 0.79 (PlGF), resulting in ~20% lower values for Kryptor PlGF. Sensitivities and specificities using the sFlt-1/PlGF ≥85 cut-off for early-onset preeclampsia (20 + 0 to 33 + 6 weeks) were 88.1%/100.0% (Elecsys®) and 90.5%/96.2% (Kryptor), respectively, and using the ≥110 cut-off for late-onset preeclampsia (≥34 + 0 weeks) were 51.3%/96.5% (Elecsys®) and 78.9%/90.1% (Kryptor), respectively. Using Elecsys® and Kryptor sFlt-1/PlGF, 0% and 3.8% of women, respectively, were falsely ruled-in for early-onset, and 3.5% and 9.9%, respectively, for late-onset preeclampsia. Conclusions Despite high correlation between the Elecsys® and Kryptor immunoassays, we observed significant differences between sFlt-1/PlGF and PlGF results. Therefore, sFlt-1/PlGF cut-offs validated for Elecsys® immunoassays are not transferable to Kryptor immunoassays.

Objectives: To evaluate the impact of age-and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI). Methods: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14 ng/L to previously proposed age-and gender-dependent hs-cTnT 99th percentile cut-offs (28 ng/L for >= 65 years, 9 ng/L for female and 15.5 ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS. Results: For patients >= 65 years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n = 557) and 54.7% to 40.9% in the ACS subcohort (n = 225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n = 477) and 62.6% to 71.7% (ACS subcohort, n = 99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n = 805) and 48.8% to 45.9% (ACS, n = 281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p < 0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs. Conclusions: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

To assess the association of a serum soluble fms-like tyrosine kinase 1-to-placental growth factor (sFlt-1-to-PlGF) ratio of greater than 38 with time to delivery and preterm birth.Secondary analysis of an observational cohort study that included women 18 years of age or older from 24 to 36 6/7 weeks of gestation at their first study visit with suspected (not confirmed) preeclampsia. Participants were recruited from December 2010 to January 2014 at 30 sites in 14 countries. A total of 1,041 women were included in time-to-delivery analysis and 848 in preterm birth analysis.Women with an sFlt-1-to-PlGF ratio greater than 38 (n=250) had a 2.9-fold greater likelihood of imminent delivery (ie, delivery on the day of the test) (Cox regression hazard ratio 2.9; P

The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear.We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks.In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3).An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

Dysregulated angiogenic factors in the maternal circulation, including high soluble fms-like tyrosine kinase-1 (sFlt-1) and low placental growth factor (PlGF), as well as their ratio (sFlt1/PlGF), have been investigated as a diagnostic and prediction marker of preeclampsia. These circulating markers may represent markers for syncytiotrohoblast stress and placentally associated pregnancy complications, which represent major threats to maternal and offspring health globally. The talk will present recently published results from the PROGNOSIS [1] , [2] study as well as discuss future potential clinical and research implications of the study findings. PROGNOSIS was a prospective, multicenter, observational study in pregnancy where preeclampsia was suspected (gestational weeks 24 to 36 + 6 days). Maternal serum sFlt-1 and PlGF were measured after delivery (the results were unknown for clinicians) using Elecsys® sFlt-1 and PlGF assays (cobas e electrochemiluminescence immunoassay platform). The results from the development and validation cohorts (n = 500 and 550 pregnancies) identified an sFlt-1/PlGF ratio cut-off of 38 to optimally predict preeclampsia and that a ratio of ⩽38 is useful for predicting short-term absence of preeclampsia in women in whom the syndrome is suspected clinically [1] . In our second PROGNOSIS published paper [2] , we found that pregnancies with an sFlt-1/PlGF ratio >38 had three-times greater likelihood of preterm delivery and a substantially shorter remaining time to delivery than women with an sFlt-1/PlGF ratio of 38 or lower, whether or not they developed preeclampsia. Women who had iatrogenic preterm delivery (without preeclampsia) had higher median sFlt-1/PlGF ratios at the first study visit versus women with spontaneous preterm or at-term delivery. Clinical implications include the need for testing whether the use of the sFlt1/PlGF ratio to guide clinical decisions, as compared with usual care, will improve clinical outcome for mother and offspring. If cost-efficient, the use of circulating biomarkers can revolutionize the obstetric surveillance in countries that can offer such follow-up.

Eine prazise Vorhersage der Praeklampsie (PE) kann dazu beitragen, mutterliche und kindliche Morbiditat und Mortalitat zu reduzieren. Der Quotient aus loslicher fms-like Tyrosinkinase 1 (sFlt-1) und plazentarem Wachstumsfaktor (PlGF) ist bei Frauen, die eine PE entwickeln, erhoht. In dieser Studie wurde der sFlt-1/PlGF-Quotient als Vorhersagemarker untersucht. In dieser doppelblinden, nicht-interventionellen Studie wurde der sFlt-1/PlGF-Quotient bei Frauen mit klinischem Verdacht auf PE (24 bis 36+6 Schwangerschaftswochen) bestimmt. Der primare Endpunkt der Studie war erstens zu zeigen, dass ein sFlt-1/PlGF-Quotient unterhalb des ermittelten Trennwerts das Auftreten von PE innerhalb von einer Woche ausschliest. Zweitens, dass ein sFlt-1/PlGF-Quotient oberhalb des Trennwerts das Auftreten von PE innerhalb von vier Wochen vorhersagt. Sekundare Endpunkte waren die Assoziation von sFlt-1/PlGF Quotient mit mutterlichen oder kindlichen Komplikationen. In einer Kohorte von 500 Patientinnen wurde ein sFlt-1/PlGF-Quotient Trennwert von 38 fur die Vorhersage der PE ermittelt. Dieser Trennwert wurde in einer Kohorte von 550 weiteren Patienten validiert. Fur die Gesamtkohorte konnte gezeigt werden, dass das Auftreten einer PE innerhalb einer Woche mit einem negativen Vorehrsagewert von 99,1% (95% Konfidenzintervall [CI], 98,2 bis 99,6), mit einer Sensitivitat von 85,7% (95% CI, 72,8 to 94,1) und einer Spezifitat von 79,1% (95% CI, 76,5 bis 81,6) ausgeschlossen werden kann. Das Auftreten einer PE innerhalb vier Wochen konnte mit einem positiven Vorhersagewert von 38,6% (95% CI, 32,6 bis 45,0), mit einer Sensitivitat von 70,3% (95% CI, 61,9 bis 77,8) und einer Spezifitat von 83,1% (95% CI, 80,5 bis 85,5) vorhergesagt werden. Hohe sFlt-1/PlGF Quotienten waren mit fetalen Komplikationen vergesellschaftet. Ein sFlt-1/PlGF Quotient < 38 kann das Auftreten einer PE innerhalb von einer Woche bei Patientinnen mit klinischem Verdacht auf Praeklampsie sicher ausschliesen.

Introduction Clinical signs and symptoms of preeclampsia are known to be poorly predictive of who will develop the condition, prompting the investigation of angiogenic biomarkers as potential diagnostic and predictive aids. The Elecsys® immunoassay soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is Conformite Europeenne-In Vitro Diagnostics approved as a diagnostic aid for preeclampsia, and as an aid in the short-term prediction of preeclampsia (rule out and rule in) in pregnant women with suspected preeclampsia in conjunction with other diagnostic and clinical information. In the Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS), a cut-off value of 38 was derived and validated to rule out preeclampsia and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome within one week (Zeisler et al. N Engl J Med 2016;374:13–22). However, the ability of the sFlt-1/PlGF ratio to rule out preeclampsia up to four weeks in women with suspected disease has not been determined. Objectives We aimed to establish the negative predictive values (NPVs) applying the Elecsys® immunoassay sFlt-1/PlGF ratio cut-off value of 38 to rule out preeclampsia within two to four weeks after testing in women with suspected preeclampsia. Methods PROGNOSIS was a prospective, observational, multicenter study, which validated the sFlt-1/PlGF ratio cut-off value of 38 to reliably rule out preeclampsia within one week in women who had clinical signs and symptoms of the syndrome (gestational age 24w+0d–36w+6d). We performed a post-hoc analysis of the data from the validation cohort of 550 participants to determine the NPV of this ratio cut-off value to rule out preeclampsia within two, three and four weeks after testing. Results A total of 550 participants from the PROGNOSIS validation cohort were included in this analysis (median age 31years; median pre-pregnancy body mass index 26.2kg/m 2 ; median systolic blood pressure 128.0mmHg; median gestation week 31w+3d; 79 (14%) were current smokers; 418 (76%) were white/Caucasian). Of these, 98 (18%) developed preeclampsia/HELLP syndrome at some point during their pregnancy: 15 (3%) within one week; 41 (7%) within two weeks; 60 (11%) within three weeks; and 71 (13%) within four weeks. The NPV to rule out preeclampsia in women with sFlt-1/PlGF values of 38 and below within two, three and four weeks of testing was 97.9% (95% confidence interval [CI]: 96.0–99.0), 95.7% (95% CI: 93.3–97.5), and 94.3% (95% CI: 91.7–96.3), respectively (Table). Conclusions This post-hoc analysis of PROGNOSIS shows that sFlt-1/PlGF ratios of 38 and below could rule out preeclampsia for up to four weeks after testing with high NPV in women with suspicion of the syndrome.

Predictive Value of the sFlt-1 : PlGF Ratio in Women With Suspected Preeclampsia EDITORIAL COMMENT

Background Preeclampsia is defined as new onset of hypertension and proteinuria at gestational week 20 or after. However, use of these measures to predict preeclampsia before its clinical onset is unreliable, and evidence suggests that preeclampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome may develop without hypertension or proteinuria being evident. Because of its unpredictability, varying clinical presentation and potential adverse outcomes, pregnant women with suspected preeclampsia require intensive monitoring or hospitalization. Beyond preeclampsia diagnosis, there is a high unmet medical need for more reliable predictive markers for preeclampsia to improve maternal and fetal outcomes and reduce unnecessary hospital admissions. An imbalance of circulating angiogenic and antiangiogenic factors, including raised soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF), has been found in women diagnosed with preeclampsia and before clinical onset of the disease. The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) was designed to investigate the use of the sFlt-1/PlGF ratio in the short-term prediction of preeclampsia. Methods/Design This global, multicenter, prospective, double-blind, non-interventional study aims to derive and validate cutoffs for the sFlt-1/PlGF ratio, to rule out (for 1 week) or rule in (within 4 weeks) the occurrence of preeclampsia/eclampsia/HELLP syndrome. Eligible participants are women presenting at 24 to

Purpose: Fecal occult blood testing is recommended as first-line screening to detect colorectal cancer (CRC). We evaluated markers and marker combinations in serum as an alternative to improve the detection of CRC. Experimental Design: Using penalized logistic regression, 6 markers were selected for evaluation in 1,027 samples (301 CRC patients, 143 patients with adenoma, 266 controls, 141 disease controls, and 176 patients with other cancer). The diagnostic performance of each marker and of marker combinations was assessed. Results: To detect CRC from serum samples, we tested 22 biomarkers. Six markers were selected for a marker combination, including the known tumor markers CEA (carcinoembryonic antigen) and CYFRA 21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin (OPN), anti-p53, and seprase. CEA showed the best sensitivity at 95% specificity with 43.9%, followed by seprase (42.4%), CYFRA 21-1 (35.5%), OPN (30.2%), ferritin (23.9%), and anti-p53 (20.0%). A combination of these markers gave 69.6% sensitivity at 95% specificity and 58.7% at 98% specificity. Focusing on International Union against Cancer (UICC) stages 0–III reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a subcollective, with matched stool samples (75 CRC cases and 234 controls), the sensitivity of the marker combination was comparable with fecal immunochemical testing (FIT) with 82.4% and 68.9% versus 81.8% and 72.7% at 95% and 98% specificity, respectively. Conclusions: The performance of the serum marker combination is comparable with FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis. Clin Cancer Res; 16(24); 6111–21. ©2010 AACR.

Impact Of Markedly Elevated Initial High -Sensitivity Cardiac Troponin T On Prediction Of Acute Myocardial Infarction In Chest Pain Patients And Additional Value Of Kinetic Changes : Results From The Trapid-AMI Study

Background: Fecal occult blood testing (FOBT) is the recommended first line screening for the detection of colorectal cancer (CRC). To improve the detection of CRC we evaluated serum markers and combinations of serum markers as an alternative approach. Methods: Applying Lasso Regression, a specialized form of penalized logistic regression, we selected six markers for an evaluation in a collective of 857 patients including 301 CRC patients, 143 patients with adenoma, 266 healthy controls and 147 disease controls. For each marker and marker combination the performance was assessed. Results: We tested a total of 22 biomarkers for the detection of CRC from serum. Of these six markers were selected for a marker combination by Lasso Regression. Included were the well-known tumor markers CEA and CYFRA21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin, anti-p53 and seprase. CEA showed the best sensitivity of all markers with 43.9 % at 95% specificity, followed by seprase (42.4%), CYFRA21-1 (35.5%), osteopontin (30.2%), ferritin (23.9%) and anti-p53 (20.0%). When these markers were combined a sensitivity of 72.3% was reached at a corresponding specificity of 95% and of 62.1% at 98% specificity. Focusing on more screening relevant stages, UICC stages 0-III, reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a sub-collective where matched stool samples were available (75 CRC cases and 234 controls) the sensitivity of the marker combination was comparable to fecal immunochemical testing (FIT) with 82.4% and 68.9% vs. 81.8% and 72.7% at 95% and 98% specificity, respectively. Conclusion: When six markers were combined to detect CRC from serum, the combination reached a performance that was comparable to FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2738.

The TRAPID-AMI study was a multicenter trial evaluating the high sensitivity cardiac troponin T (hs-cTnT) assay in a rapid “rule-out” acute myocardial infarction (AMI) strategy in the Emergency Department (ED). We evaluated a modified HEART score (HS) to identify a low-risk group that involves

STUDY OBJECTIVE: We aim to prospectively validate the diagnostic accuracy of the recently developed 0-h/1-h algorithm, using high-sensitivity cardiac troponin T (hs-cTnT) for the early rule-out and rule-in of acute myocardial infarction.METHODS: We enrolled patients presenting with suspected acute myocardial infarction and recent (RESULTS: Among 1,282 patients enrolled, acute myocardial infarction was the final diagnosis for 213 (16.6%) patients. Applying the hs-cTnT 0-hour/1-hour algorithm, 813 (63.4%) patients were classified as rule out, 184 (14.4%) were classified as rule in, and 285 (22.2%) were triaged to the observational zone. This resulted in a negative predictive value and sensitivity for acute myocardial infarction of 99.1% (95% confidence interval [CI] 98.2% to 99.7%) and 96.7% (95% CI 93.4% to 98.7%) in the rule-out zone (7 patients with false-negative results), a positive predictive value and specificity for acute myocardial infarction of 77.2% (95% CI 70.4% to 83.0%) and 96.1% (95% CI 94.7% to 97.2%) in the rule-in zone, and a prevalence of acute myocardial infarction of 22.5% in the observational zone.CONCLUSION: The hs-cTnT 0-hour/1-hour algorithm performs well for early rule-out and rule-in of acute myocardial infarction.