Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia.

Current diagnostic criteria have limited clinical value for prediction of preeclampsia and fetal adverse outcomes. The prediction of short-term outcome in pregnant women with suspected preeclampsia study in Asia (PROGNOSIS Asia) was a prospective, multicenter study designed to investigate the value of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio for predicting adverse outcomes in pregnant Asian women with suspected preeclampsia. Seven hundred sixty-four pregnant women at gestational week 20+0 days (18+0 days in Japan) to 36+6 days were enrolled at 25 sites in Asia. The primary objectives were to demonstrate the value of the sFlt-1/PlGF ratio for ruling out preeclampsia within 1 week and ruling in preeclampsia within 4 weeks. The value of the ratio for predicting fetal adverse outcomes was also assessed. Seven hundred patients were evaluable for primary end point analysis. The prevalence of preeclampsia was 14.4%. An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.6% (95% CI, 97.2%-99.4%) for ruling out preeclampsia within 1 week, with 76.5% sensitivity and 82.1% specificity. The positive predictive value of a ratio of >38 for ruling in preeclampsia within 4 weeks was 30.3% (95% CI, 23.0%-38.5%), with 62.0% sensitivity and 83.9% specificity. An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.9% (95% CI, 97.6%-99.6%) for ruling out fetal adverse outcomes within 1 week and a ratio of >38 had a positive predictive value of 53.5% (95% CI, 45.0%-61.8%) for ruling in fetal adverse outcomes within 4 weeks. The sFlt-1/PlGF ratio cutoff of 38 demonstrated clinical value for the short-term prediction of preeclampsia in Asian women with suspected preeclampsia, potentially helping to prevent unnecessary hospitalization and intervention.

A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count.

RESEARCH QUESTION: What concentration of anti-Müllerian hormone (AMH) corresponds to an antral follicle count (AFC) >15 for determination of ovarian reserve? DESIGN: A prospective study conducted at 13 US fertility clinics in women aged 21-44 years who presented for AFC evaluation by transvaginal ultrasound. Serum samples were collected at the time of AFC evaluation (menstrual cycle day 2-4). AMH concentrations were measured by the Elecsys® AMH immunoassay; oestradiol and follicle-stimulating hormone (FSH) concentrations were also measured. The serum AMH cut-off able to detect AFC >15 with high sensitivity was determined (derivation cohort). Clinical performance of the AMH assay at the derived cut-off was evaluated (validation cohort). Receiver operating characteristic (ROC) analyses were also performed. RESULTS: In the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC >15 with 89.63% sensitivity and 69.01% specificity, using the Elecsys AMH assay. In the validation cohort (n = 856), this 1.77 ng/ml cut-off could identify women with an AFC >15 with a sensitivity of 88.34% and a specificity of 68.29%; corresponding positive predictive and negative predictive values were 75.19% and 84.34%, respectively. ROC analyses demonstrated that AMH performed better than oestradiol or FSH in predicting AFC, with area under the curves of 85.7%, 57.1% and 69.7%, respectively, in the validation cohort. CONCLUSION: The Elecsys AMH immunoassay provides a robust and fully automated method to measure serum AMH levels. Women with AMH values below the cut-off of 1.77 ng/ml are unlikely to have AFC >15.

Serum Anti-Müllerian Hormone Is Significantly Altered by Downregulation With Daily Gonadotropin-Releasing Hormone Agonist: A Prospective Cohort Study.

Research Question: What is the effect of gonadotropin-releasing hormone (GnRH)-agonist treatment on serum anti-Müllerian hormone (AMH)? Design: This prospective cohort study conducted in a tertiary university hospital comprised patients (n = 52) who self-administered daily triptorelin (0.1 mg/0.1 mL) subcutaneously for 14 days from menstrual cycle day 21 ± 3, between July 2015 and March 2016. Enrolled women were 18-43 years old, considered normal ovarian responders, with a planned GnRH agonist controlled ovarian stimulation protocol. The primary endpoint was to evaluate the effect of GnRH agonist on serum AMH levels after 7 and 14 days of treatment. Results: Under GnRH agonist treatment, serum AMH was significantly decreased vs. baseline on day 7 (mean change from baseline: -0.265 ng/mL; 95% confidence interval [CI], -0.395 to -0.135 ng/mL; p < 0.001). On day 14, serum AMH was significantly increased (mean change from baseline: 0.289 ng/mL; 95% CI, 0.140-0.439 ng/mL; p < 0.001). Although the median change in AMH from baseline was only -14.9% on day 7 and +17.4% on day 14, from day 7 to 14 AMH significantly increased by 0.55 ng/mL (43.8%; p < 0.001), which is of paramount clinical importance. A linear, mixed-effect model demonstrated that GnRH agonist treatment for 7 and 14 days had a highly significant effect on serum AMH concentration after adjustment for confounding factors (age, body mass index, baseline antral follicle count, and visit). AMH assay precision was excellent (four aliquots/sample); coefficient of variation was 1.2-1.4%. Conclusions: GnRH agonist treatment had a clinically significant effect on serum AMH, dependent on treatment duration. The clear V-shaped response of AMH level to daily GnRH agonist treatment has important clinical implications for assessing ovarian reserve and predicting ovarian response, thus AMH measurements under GnRH agonist downregulation should be interpreted with great caution.

Biomarker development targeting unmet clinical needs.

BACKGROUND: The introduction of new biomarkers can lead to inappropriate utilization of tests if they do not fill in existing gaps in clinical care. We aimed to define a strategy and checklist for identifying unmet needs for biomarkers. METHODS: A multidisciplinary working group used a 4-step process: 1/ scoping literature review; 2/ face-to-face meetings to discuss scope, strategy and checklist items; 3/ iterative process of feedback and consensus to develop the checklist; 4/ testing and refinement of checklist items using case scenarios. RESULTS: We used clinical pathway mapping to identify clinical management decisions linking biomarker testing to health outcomes and developed a 14-item checklist organized into 4 domains: 1/ identifying and 2/ verifying the unmet need; 3/ validating the intended use; and 4/ assessing the feasibility of the new biomarker to influence clinical practice and health outcome. We present an outcome-focused approach that can be used by multiple stakeholders for any medical test, irrespective of the purpose and role of testing. CONCLUSIONS: The checklist intends to achieve more efficient biomarker development and translation into practice. We propose the checklist is field tested by stakeholders, and advocate the role of the clinical laboratory professional to foster trans-sector collaboration in this regard.

Influence of the sFlt-1/PlGF Ratio on Clinical Decision-Making in Women with Suspected Preeclampsia.

OBJECTIVE: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians' decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice. METHODS: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad® application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome. RESULTS: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001). CONCLUSIONS: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice.

Setting analytical performance specifications based on outcome studies - is it possible?

The 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine proposed a simplified hierarchy for setting analytical performance specifications (APS). The top two levels of the 1999 Stockholm hierarchy, i.e., evaluation of the effect of analytical performance on clinical outcomes and clinical decisions have been proposed to be replaced by one outcome-based model. This model can be supported by: (1a) direct outcome studies; and (1b) indirect outcome studies investigating the impact of analytical performance of the test on clinical classifications or decisions and thereby on the probability of patient relevant clinical outcomes. This paper reviews the need for outcome-based specifications, the most relevant types of outcomes to be considered, and the challenges and limitations faced when setting outcome-based APS. The methods of Model 1a and b are discussed and examples are provided for how outcome data can be translated to APS using the linked evidence and simulation or decision analytic techniques. Outcome-based APS should primarily reflect the clinical needs of patients; should be tailored to the purpose, role and significance of the test in a well defined clinical pathway; and should be defined at a level that achieves net health benefit for patients at reasonable costs. Whilst it is acknowledged that direct evaluations are difficult and may not be possible for all measurands, all other forms of setting APS should be weighed against that standard, and regarded as approximations. Better definition of the relationship between the analytical performance of tests and health outcomes can be used to set analytical performance criteria that aim to improve the clinical and cost-effectiveness of laboratory tests.

From biomarkers to medical tests: the changing landscape of test evaluation.

Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use. This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost-effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes. The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests.