Cancer biomarkers: Emerging trends and clinical implications for personalized treatment.

The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.

Construction of a comprehensive fetal monitoring database for the study of perinatal hypoxic ischemic encephalopathy.

This article describes the methods used to build a large-scale database of more than 250,000 electronic fetal monitoring (EFM) records linked to a comprehensive set of clinical information about the infant, the mother, the pregnancy, labor, and outcome. The database can be used to investigate how birth outcome is related to clinical and EFM features. The main steps involved in building the database were: (1) Acquiring the raw EFM recording and clinical records for each birth. (2) Assigning each birth to an objectively defined outcome class that included normal, acidosis, and hypoxic-ischemic encephalopathy. (3) Removing all personal health information from the EFM recordings and clinical records. (4) Preprocessing the deidentified EFM records to eliminate duplicates, reformat the signals, combine signals from different sensors, and bridge gaps to generate signals in a format that can be readily analyzed. (5) Post-processing the repaired EFM recordings to extract key features of the fetal heart rate, uterine activity, and their relations. (6) Populating a database that links the clinical information, EFM records, and EFM features to support easy querying and retrieval. •A multi-step process is required to build a comprehensive database linking electronic temporal fetal monitoring signals to a comprehensive set of clinical information about the infant, the mother, the pregnancy, labor, and outcome.•The current database documents more than 250,000 births including almost 4,000 acidosis and 400 HIE cases. This represents more than 80% of the births that occurred in 15 Northern California Kaiser Permanente Hospitals between 2011-2019. This is a valuable resource for studying the factors predictive of outcome.•The signal processing code and schemas for the database are freely available. The database will not be permitted to leave Kaiser firewalls, but a process is in place to allow interested investigators to access it.

New labor curves of dilation and station to improve the accuracy of predicting labor progress.

BACKGROUND: The diagnosis of failure to progress, the most common indication for intrapartum cesarean delivery, is based on the assessment of cervical dilation and station over time. Labor curves serve as references for expected changes in dilation and fetal descent. The labor curves of Friedman, Zhang et al, and others are based on time alone and derived from mothers with spontaneous labor onset. However, labor induction is now common, and clinicians also consider other factors when assessing labor progress. Labor curves that consider the use of labor induction and other factors that influence labor progress have the potential to be more accurate and closer to clinical decision-making. OBJECTIVE: This study aimed to compare the prediction errors of labor curves based on a single factor (time) or multiple clinically relevant factors using two modeling methods: mixed-effects regression, a standard statistical method, and Gaussian processes, a machine learning method. STUDY DESIGN: This was a longitudinal cohort study of changes in dilation and station based on data from 8022 births in nulliparous women with a live, singleton, vertex-presenting fetus ≥35 weeks of gestation with a vaginal delivery. New labor curves of dilation and station were generated with 10-fold cross-validation. External validation was performed using a geographically independent group. Model variables included time from the first examination in the 20 hours before delivery; dilation, effacement, and station recorded at the previous examination; cumulative contraction counts; and use of epidural anesthesia and labor induction. To assess model accuracy, differences between each model's predicted value and its corresponding observed value were calculated. These prediction errors were summarized using mean absolute error and root mean squared error statistics. RESULTS: Dilation curves based on multiple parameters were more accurate than those derived from time alone. The mean absolute error of the multifactor methods was better (lower) than those of the single-factor methods (0.826 cm [95% confidence interval, 0.820-0.832] for the multifactor machine learning and 0.893 cm [95% confidence interval, 0.885-0.901] for the multifactor mixed-effects method and 2.122 cm [95% confidence interval, 2.108-2.136] for the single-factor methods; P<.0001 for both comparisons). The root mean squared errors of the multifactor methods were also better (lower) than those of the single-factor methods (1.126 cm [95% confidence interval, 1.118-1.133] for the machine learning [P<.0001] and 1.172 cm [95% confidence interval, 1.164-1.181] for the mixed-effects methods and 2.504 cm [95% confidence interval, 2.487-2.521] for the single-factor [P<.0001 for both comparisons]). The multifactor machine learning dilation models showed small but statistically significant improvements in accuracy compared to the mixed-effects regression models (P<.0001). The multifactor machine learning method produced a curve of descent with a mean absolute error of 0.512 cm (95% confidence interval, 0.509-0.515) and a root mean squared error of 0.660 cm (95% confidence interval, 0.655-0.666). External validation using independent data produced similar findings. CONCLUSION: Cervical dilation models based on multiple clinically relevant parameters showed improved (lower) prediction errors compared to models based on time alone. The mean prediction errors were reduced by more than 50%. A more accurate assessment of departure from expected dilation and station may help clinicians optimize intrapartum management.

Data-Driven Insights into Labor Progression with Gaussian Processes.

Clinicians routinely perform pelvic examinations to assess the progress of labor. Clinical guidelines to interpret these examinations, using time-based models of cervical dilation, are not always followed and have not contributed to reducing cesarean-section rates. We present a novel Gaussian process model of labor progress, suitable for real-time use, that predicts cervical dilation and fetal station based on clinically relevant predictors available from the pelvic exam and cardiotocography. We show that the model is more accurate than a statistical approach using a mixed-effects model. In addition, it provides confidence estimates on the prediction, calibrated to the specific delivery. Finally, we show that predicting both dilation and station with a single Gaussian process model is more accurate than two separate models with single predictions.

Examining Attitudes Towards Mental Health Diagnoses: A Q-Methodology Study.

BACKGROUND: Debates exist regarding the validity and utility of functional psychiatric diagnoses. How mental health diagnoses are understood has real impacts for service users and service delivery. AIMS: To investigate different attitudes about the utility of psychiatric diagnoses. METHODS: Forty-one stakeholders sorted 57 statements related to the usefulness of psychiatric diagnoses. Using q-methodology, four viewpoints were identified and interpreted. RESULTS: Viewpoint 1 (Pathologising human experience) regarded diagnoses as pseudo-scientific constructs that lacked validity and obscured the relationships between lived experience and distress. Viewpoint 2 (Illnesses like any other) held that labels reflected real disorders and diagnosis offered important benefits for service users and services. Viewpoint 3 (Stigmatised conditions) similarly regarded diagnoses as reflecting real disorders, but diagnostic criteria were viewed as biased and the impacts of applying labels seen as causing problems for service users. Conversely, Viewpoint 4 (Useful short-hands) viewed diagnostic processes as imperfect but necessary for supporting communication and structuring service delivery. CONCLUSIONS: While not all viewpoints are in keeping with empirical evidence, we hope results will enable professionals and service users to take meta-positions in relation to their own and others' attitudes, and to reflect on the impacts of privileging certain viewpoints over others.

Timely Detection of Infants at Risk of Intrapartum Acidosis and Hypoxic-Ischemic Encephalopathy Using Cardiotocography.

This work aims to improve the intrapartum detection of fetuses with an increased risk of developing fetal acidosis or hypoxic-ischemic encephalopathy (HIE) using fetal heart rate (FHR) and uterine pressure (UP) signals. Our study population comprised 40,831 term births divided into 3 classes based on umbilical cord or early neonatal blood gas assessments: 374 with verified HIE, 3,047 with acidosis but no encephalopathy and 37,410 healthy babies with normal gases. We developed an intervention recommendation system based on a random forest classifier. The classifier was trained using classical and novel features extracted electronically from 20-minute epochs of FHR and UP. Then, using the predictions of the classifier on each epoch, we designed a decision rule to determine when to recommended intervention. Compared to the Caesarean rates in each study group, our system identified an additional 5.68% of babies who developed HIE (54.55% vs 60.23%, p < 0.01) with a specific alert threshold. Importantly, about 75% of these recommendations were made more than 200 minutes before birth. In the acidosis group, the system identified an additional 17.44% (37.15% vs 54.59%, p < 0.01) and about 2/3 of these recommendations were made more than 200 minutes before birth. Compared to the Caesarean rate in the healthy group, the associated false positive rate was increased by 1.07% (38.80% vs 39.87%, p<0.01).Clinical Relevance- This method recommended intervention in more babies affected by acidosis or HIE, than the intervention rate observed in practice and most often did so 200 minutes before delivery. This was early enough to expect that interventions would have clinical benefit and reduce the rate of HIE. Given the high burden associated with HIE, this would justify the marginal increase in the normal Cesarean rate.

Accounting for Nulliparity in the Prediction of Hypoxic-Ischemic Encephalopathy Using Cardiotocography.

Nulliparous pregnancies, those where the mother has not previously given birth, are associated with longer labors and hence expose the fetus to more contractions and other adverse intrapartum conditions such as chorioamnionitis. The objective of the present study was to test if accounting for nulliparity could improve the detection of fetuses at increased risk of developing hypoxic-ischemic encephalopathy (HIE). During labor, clinicians assess the fetal heart rate and uterine pressure signals to identify fetuses at risk of developing HIE. In this study, we performed random forest classification using fetal heart rate and uterine pressure features from 40,831 births, including 374 that developed HIE. We analyzed a two-path classification approach that analyzed separately the fetuses from nulliparous and multiparous mothers, and a one-path classification approach that included the clinical variable for nulliparity as a classification feature. We compared these two approaches to a one-path classifier that had no information about the parity of the mothers. We also compared our results to the rate of Caesarean deliveries in each group, which is used clinically to interrupt the progression towards HIE. All the classifiers detected more fetuses that developed HIE than the observed Caesarean rate, but accounting for nulliparity did not improve performance.

Perinatal Hypoxic-Ischemic Encephalopathy: Incidence Over Time Within a Modern US Birth Cohort.

BACKGROUND: Recent studies suggest that the incidence of perinatal hypoxic-ischemic encephalopathy (HIE) may be increasing in developed countries. However, this observed increase may be due to increased ascertainment and increased treatment with therapeutic hypothermia rather than an increase in disease burden. In a US population-based cross-sectional study, we determined the incidence of perinatal HIE over time. METHODS: The study population included all 289,793 live-born infants ≥35 weeks gestational age born at 15 Kaiser Permanente Northern California hospitals between 2012 and 2019. Perinatal HIE was defined as the presence of both neonatal acidosis (i.e., cord blood pH < 7 or base deficit ≥10, or base deficit ≥10 on first infant gas) and neonatal encephalopathy confirmed by medical record review. Hospital discharge diagnoses of HIE were determined by extracting International Classification of Disease diagnostic codes for HIE assigned upon hospital discharge. RESULTS: The population incidence of perinatal HIE was 1.7 per 1000. Although the incidence of perinatal HIE did not change significantly, both hospital discharge diagnoses of HIE and treatment with therapeutic hypothermia increased significantly during the study period. The sensitivity and positive predictive value of a hospital discharge diagnosis of HIE for identifying perinatal HIE confirmed by chart review were 72% and 79%, respectively. CONCLUSIONS: During the study years, the incidence of perinatal HIE remained stable despite increases in hospital discharge diagnoses of HIE and in the use of therapeutic hypothermia. Our findings underscore the importance of applying stringent diagnostic criteria when diagnosing this complex condition.

The evolution of the labor curve and its implications for clinical practice: the relationship between cervical dilation, station, and time during labor.

The assessment of labor progress is germane to every woman in labor. Two labor disorders-arrest of dilation and arrest of descent-are the primary indications for surgery in close to 50% of all intrapartum cesarean deliveries and are often contributing indications for cesarean deliveries for fetal heart rate abnormalities. Beginning in 1954, the assessment of labor progress was transformed by Friedman. He published a series of seminal works describing the relationship between cervical dilation, station of the presenting part, and time. He proposed nomenclature for the classification of labor disorders. Generations of obstetricians used this terminology and normal labor curves to determine expected rates of dilation and fetal descent and to decide when intervention was required. The analysis of labor progress presents many mathematical challenges. Clinical measurements of dilation and station are imprecise and prone to variation, especially for inexperienced observers. Many interrelated factors influence how the cervix dilates and how the fetus descends. There is substantial variability in when data collection begins and in the frequency of examinations. Statistical methods to account for these issues have advanced considerably in recent decades. In parallel, there is growing recognition among clinicians of the limitations of using time alone to assess progress in cervical dilation in labor. There is wide variation in the patterns of dilation over time and most labors do not follow an average dilation curve. Reliable assessment of labor progression is important because uncertainty leads to both over-use and under-use of cesarean delivery and neither of these extremes are desirable. This review traces the evolution of labor curves, describes how limitations are being addressed to reduce uncertainty and to improve the assessment of labor progression using modern statistical techniques and multi-dimensional data, and discusses the implications for obstetrical practice.

Perinatal Outcome following the Suspension of Intrapartum Oxygen Treatment.

OBJECTIVE: This study aimed to evaluate whether the suspension of intrapartum maternal oxygen supplementation for nonreassuring fetal heart rate is associated with adverse perinatal outcomes. STUDY DESIGN: A retrospective cohort study, including all individuals that underwent labor in a single tertiary medical center. On April 16, 2020, the routine use of intrapartum oxygen for category II and III fetal heart rate tracings was suspended. The study group included individuals with singleton pregnancies that underwent labor during the 7 months between April 16, 2020, and November 14, 2020. The control group included individuals that underwent labor during the 7 months before April 16, 2020. Exclusion criteria included elective cesarean section, multifetal pregnancy, fetal death, and maternal oxygen saturation <95% during delivery. The primary outcome was defined as the rate of composite neonatal outcome, consisting of arterial cord pH <7.1, mechanical ventilation, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage grade 3/4, and neonatal death. The secondary outcome was the rate of cesarean and operative delivery. RESULTS: The study group included 4,932 individuals, compared with 4,906 individuals in the control group. The suspension of intrapartum oxygen treatment was associated with a significant increase in the rate of composite neonatal outcome (187 [3.8%] vs. 120 [2.4%], p < 0.001), including the rate of abnormal cord arterial pH <7.1 (119 [2.4%] vs. 56 [1.1%], p < 0.01). A higher rate of cesarean section due to nonreassuring fetal heart rate was noted in the study group (320 [6.5%] vs. 268 [5.5%], p = 0.03).A logistic regression analysis revealed that the suspension of intrapartum oxygen treatment was independently associated with the composite neonatal outcome (adjusted odds ratio = 1.55 [95% confidence interval, 1.23-1.96]) while adjusting for suspected chorioamnionitis, intrauterine growth restriction, and recent coronavirus disease 2019 exposure. CONCLUSION: Suspension of intrapartum oxygen treatment for nonreassuring fetal heart rate was associated with higher rates of adverse neonatal outcomes and urgent cesarean section due to fetal heart rate. KEY POINTS: · The available data on intrapartum maternal oxygen supplementation are equivocal.. · Suspension of maternal oxygen for nonreassuring fetal heart rate during labor was associated with adverse neonatal outcomes.. · Oxygen treatment might still be important and relevant during labor..

Evaluating the Addition of Clinical and Staging Data to Improve the Pricing Methodology of the Oncology Care Model.

PURPOSE: The Oncology Care Model (OCM) is the largest value-based care model focusing on oncology, but the current pricing methodology excludes relevant data on the cancer stage and current clinical status, limiting the precision of the risk adjustment. METHODS: This analysis evaluated 15,580 episodes of breast cancer, lung cancer, and multiple myeloma, starting between July 1, 2016, and January 1, 2020, with data from a cohort of OCM practices affiliated with academic medical centers. The authors merged clinical data with claims for OCM episodes defined by the Center for Medicare and Medicaid Innovation to identify potential quality improvement opportunities. The regression model evaluated the association of the cancer stage at initial diagnosis and current clinical status with variance to the OCM target price. RESULTS: Cancer stage at the time of initial diagnosis was significant for breast and lung cancers, with stage IV episodes having the highest losses of -$6,700 (USD) for breast cancer (P < .001) and -$18,470 (USD) for lung cancer (P < .001). Current clinical status had a significant impact for all three cancers in the analysis, with losses correlated with clinical complexity. Breast cancer and multiple myeloma episodes categorized as recurrent or progressive disease had significantly higher losses than stable episodes, at -$6,755 (USD) for breast (P < .001) and -$19,448 (USD) for multiple myeloma (P < .001). Lung cancer episodes categorized as initial diagnosis had significantly fewer losses than stable episodes, at -$3,751 (USD) (P = .001). CONCLUSION: As the Center for Medicare and Medicaid Innovation designs and launches new oncology-related models, the agency should adopt methodologies that more accurately set target prices, by incorporating relevant clinical data within cancer types to minimize penalizing practices that provide guideline-concordant cancer care.

Multi-Chain Semi-Markov Analysis of Intrapartum Cardiotocography.

Visual assessment of the evolution of fetal heart rate (FHR) and uterine pressure (UP) patterns is the standard of care in the intrapartum period. Unfortunately, this assessment has high levels of intra- and inter-observer variability. This study processed and analyzed FHR and UP patterns using computerized pattern recognition tools. The goal was to evaluate differences in FHR and UP patterns between fetuses with normal outcomes and those who developed hypoxic-ischemic encephalopathy (HIE). For this purpose, we modeled the sequence of FHR patterns and uterine contractions using Multi-Chain Semi-Markov models (MCSMMs). These models estimate the probability of transitioning between FHR or UP patterns and the dwell time of each pattern. Our results showed that in comparison to the control group, the HIE group had: (1) more frequent uterine contractions during the last 12 hours before birth; (2) more frequent FHR decelerations during the last 12 hours before birth; (3) longer decelerations during the last eight hours before birth; and (4) shorter baseline durations during the last five hours before birth. These results demonstrate that the fetuses in the HIE group were subject to a more stressful environment than those in the normal group. Clinical Relevance- Our results revealed statistically significant differences in FHR/UP patterns between the normal and HIE groups in the hours before birth. This indicates that features derived using MCSMMs may be useful in a machine learning framework to detect infants at increased risk of developing HIE allowing preventive interventions.

Inferring gene expression from cell-free DNA fragmentation profiles.

Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.

The Nonlinear Dynamic Response of Intrapartum Fetal Heart Rate to Uterine Pressure.

The research objective of our group is to improve the intrapartum detection of cardiotocography tracings associated with an increased risk of developing fetal acidosis and subsequent hypoxic-ischemic encephalopathy (HIE). The detection methods that we aim to develop must be sensitive to abnormal tracings without causing excessive unnecessary interventions. Past studies showed that the dynamic response of fetal heart rate (FHR) to uterine pressure (UP) during the intrapartum could be modelled using linear systems. In this study, we examined the assumption of linearity by comparing the performance of linear dynamic and nonlinear dynamic models of the UP-FHR system. The linear systems were defined by second-order state-space models. The nonlinear systems were defined by Hammerstein models: a cascade of a static nonlinearity and a linear second-order state-space model. Our results showed that nonlinear dynamic models were better than linear systems in 81.8% of UP-FHR segments.

A Comprehensive Circulating Tumor DNA Assay for Detection of Translocation and Copy-Number Changes in Pediatric Sarcomas.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

Cumulative deceleration area: a simplified predictor of metabolic acidemia.

OBJECTIVE: Fetal monitoring, ubiquitous in obstetrics is used to predict and prevent intrapartum fetal injury. Despite decades of education and nomenclature revision, clinicians show low agreement on key elements, including the types of deceleration and hence their presumed etiology. Cumulative deceleration area is not dependent on deceleration type and could potentially mitigate this problem. Although deceleration area has shown promise as a marker of acidemia, no reports have shown how deceleration area evolves in late labor. Advances in computerization allow for direct measurement of deceleration area and standard fetal heart rate (FHR) patterns. The objective of this study was to compare the evolution and discrimination performance of deceleration area and other FHR patterns in late labor in term neonates with metabolic acidemia (MA) and in those with normal cord gases. METHODS: This retrospective cohort study included women with a term singleton (≥37 weeks) in cephalic presentation with cord gas data and FHR tracings available for analysis. MA included neonates with an umbilical artery base deficit >12 mmol/L (n = 132). Controls included those with normal cord gases (base deficit <8 mmol/L) and a 5-minute Apgar score of >6 (n = 1498). Deceleration area and other FHR patterns were summarized and compared in 30-minute segments over the last five hours. Receiver-operating characteristic curves were constructed and AUCs compared. RESULTS: Deceleration area had the highest AUC (0.702, 95% CI 0.655-0.749) and was a superior marker of MA compared to baseline (AUC 0.588, 95% CI 0.530-0.645), baseline variability (AUC 0.611, 95% CI 0.558-0.663), and number of late decelerations (AUC 0.582, 95% CI 0.527-0.637). CONCLUSION: Cumulative deceleration area reduces the necessity to determine deceleration type. In a single number, it objectively quantifies three important aspects of decelerations; frequency, depth and duration and was a superior marker of MA compared to baseline level, baseline variability and number of late decelerations. The acidemia group had higher deceleration area over the last two hours prior to delivery. This result indicates that the cumulative area and persistence of repetitive decelerations is important clinically.