Metabolic Syndrome and Morbid Obesity are Not Risk Factors for Revision Surgery in Patients Undergoing Hip and Knee Arthroplasty.

BACKGROUND: The effect of metabolic syndrome (MetS) on the risk of revision after hip and knee arthroplasty is debated. The aim of our study was to investigate the risk of short-term (minimum 2.7 years) revision due to periprosthetic joint infection (PJI) after hip and knee arthroplasty. Secondly, we aimed to investigate the risk of revision due to any cause and mortality. METHODS: During May 2017 to November 2019, a cohort of 2,901 patients undergoing a total of 3,024 hip and knee arthroplasties was established. In the cohort, 62.1% met the criteria for MetS. Data from national registries and a local database were used to determine the presence of MetS and revision surgeries, with a follow-up of at least two years and eight months. Cox regression was applied to the present hazard ratio (HR), associated 95% confidence intervals, and P values. Survival analyses were presented in a Kaplan-Meier plot. RESULTS: The risk of PJI (HR 1.6 (0.5 to 4.9), P = .380), any revision (HR 0.8 (0.4 to 1.3), P = .295), and death (HR 1.3 (0.8 to 2.1), P = .282) was not increased in patients suffering from MetS compared with patients who did not have MetS. There was no PJI in patients not having MetS and receiving a knee arthroplasty. The risk of death was increased in the MetS group receiving a knee arthroplasty (HR 2.7 (1.3 to 5.9), P = .010), but not different from the MetS group receiving a hip arthroplasty. There was no elevated risk of PJI when analyzing morbid obesity (body mass index over 40), men, or diabetes as the exposures. CONCLUSIONS: Patients suffering from MetS do not have an increased risk of revision caused by PJI. In general, performing hip and knee arthroplasty in patients suffering from MetS is without increased risk of revision surgery.

Diagnostic Performance of Plasma SP-D, KL-6, and CC16 in Acutely Hospitalised Patients Suspected of Having Community-Acquired Pneumonia-A Diagnostic Accuracy Study.

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients' final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia.

Exploring the biology of ctDNA release in colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a promising tool for early cancer detection and minimal residual disease monitoring. However, the biology underlying ctDNA release and its variation across cancer types and histologies remains poorly understood. This study investigated the biology behind ctDNA shedding in colorectal cancer. METHODS: The study included a local cohort of 747 stage I-III colorectal cancer patients. All patients had ctDNA measurement prior to treatment and extensive clinical data. Primary tumor RNA sequencing and whole exome sequencing was performed in 95 and 652 patients respectively. Additionally, the study evaluated 89 non-small cell lung cancer patients from the TRACERx cohort, comprising primary tumor RNA sequencing and ctDNA measurement. RESULTS: We found tumor size and proliferative capacity to be key factors associated with ctDNA shedding in colorectal cancer. Furthermore, we found that the secretory and CMS3 colorectal cancer subtypes exhibited lower ctDNA shedding, while microsatellite instability (MSI) tumors had higher levels of ctDNA. Mutational analysis did not reveal any genes or pathways associated with ctDNA shedding in colorectal cancer. A comparison of transcriptomic profiles across multiple cancer types demonstrated that colorectal cancer and lung squamous cell carcinoma tumors shared a high-proliferative ctDNA shedding phenotype, while lung adenocarcinoma tumors displayed a distinct low-proliferative subgroup. Additionally, proliferation levels correlated with ctDNA detection sensitivity across multiple cancer types. CONCLUSION: These findings suggest that tumor size and proliferative capacity are drivers of ctDNA release in colorectal cancer and provide insights into the biology of ctDNA shedding on a pan-cancer level.

Beyond basics: Key mutation selection features for successful tumor-informed ctDNA detection.

Tumor-informed mutation-based approaches are frequently used for detection of circulating tumor DNA (ctDNA). Not all mutations make equally effective ctDNA markers. The objective was to explore if prioritizing mutations using mutational features-such as cancer cell fraction (CCF), multiplicity, and error rate-would improve the success rate of tumor-informed ctDNA analysis. Additionally, we aimed to develop a practical and easily implementable analysis pipeline for identifying and prioritizing candidate mutations from whole-exome sequencing (WES) data. We analyzed WES and ctDNA data from three tumor-informed ctDNA studies, one on bladder cancer (Cohort A) and two on colorectal cancer (Cohorts I and N). The studies included 390 patients. For each patient, a unique set of mutations (median mutations/patient: 6, interquartile 13, range: 1-46, total n = 4023) were used as markers of ctDNA. The tool PureCN was used to assess the CCF and multiplicity of each mutation. High-CCF mutations were detected more frequently than low-CCF mutations (Cohort A: odds ratio [OR] 20.6, 95% confidence interval [CI] 5.72-173, p = 1.73e-12; Cohort I: OR 2.24, 95% CI 1.44-3.52, p = 1.66e-04; and Cohort N: OR 1.78, 95% CI 1.14-2.79, p = 7.86e-03). The detection-likelihood was additionally improved by selecting mutations with multiplicity of two or above (Cohort A: OR 1.55, 95% CI 1. 14-2.11, p = 3.85e-03; Cohort I: OR 1.78, 95% CI 1.23-2.56, p = 1.34e-03; and Cohort N: OR 1.94, 95% CI 1.63-2.31, p = 2.83e-14). Furthermore, selecting the mutations for which the ctDNA detection method had the lowest error rates, additionally improved the detection-likelihood, particularly evident when plasma cell-free DNA tumor fractions were below 0.1% (p = 2.1e-07). Selecting mutational markers with high CCF, high multiplicity, and low error rate significantly improve ctDNA detection likelihood. We provide free access to the analysis pipeline enabling others to perform qualified prioritization of mutations for tumor-informed ctDNA analysis.

Analytical Performance Specifications for Input Variables: Investigation of the Model of End-Stage Liver Disease.

BACKGROUND: Artificial intelligence models constitute specific uses of analysis results and, therefore, necessitate evaluation of analytical performance specifications (APS) for this context specifically. The Model of End-stage Liver Disease (MELD) is a clinical prediction model based on measurements of bilirubin, creatinine, and the international normalized ratio (INR). This study evaluates the propagation of error through the MELD, to inform choice of APS for the MELD input variables. METHODS: A total of 6093 consecutive MELD scores and underlying analysis results were retrospectively collected. "Desirable analytical variation" based on biological variation as well as current local analytical variation was simulated onto the data set as well as onto a constructed data set, representing a worst-case scenario. Resulting changes in MELD score and risk classification were calculated. RESULTS: Biological variation-based APS in the worst-case scenario resulted in 3.26% of scores changing by ≥1 MELD point. In the patient-derived data set, the same variation resulted in 0.92% of samples changing by ≥1 MELD point, and 5.5% of samples changing risk category. Local analytical performance resulted in lower reclassification rates. CONCLUSIONS: Error propagation through MELD is complex and includes population-dependent mechanisms. Biological variation-derived APS were acceptable for all uses of the MELD score. Other combinations of APS can yield equally acceptable results. This analysis exemplifies how error propagation through artificial intelligence models can become highly complex. This complexity will necessitate that both model suppliers and clinical laboratories address analytical performance specifications for the specific use case, as these may differ from performance specifications for traditional use of the analyses.

No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study.

OBJECTIVE: Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis. METHODS: Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52 weeks of vitamin K (MK-7, 360 µg/daily, n = 61) or placebo (n = 62). Measurements at baseline and after 52 weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1 + 2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52 weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher's exact test or Pearson's Chi-Squared test. RESULTS: A between-group difference at 52 weeks was observed for PIVKA-II (P < .001). PIVKA-II decreased significantly from baseline to 52 weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P = .04), and no between-group differences in adverse events and serious adverse events. CONCLUSION: One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment.

Hybrid CMOS detectors for high-speed X-ray imaging.

Hybrid CMOS (hCMOS) x-ray framing cameras are a new and powerful detector option for experiments in the fields of Inertial Confinement Fusion (ICF) and High Energy Density Physics (HEDP). These digital cameras capture multiple images along a single line-of-sight with a time resolution as short as 1.5 ns and with high quantum efficiency. To manage the high data rate, an image sequence is acquired in a short burst of time and subsequently read out on a much longer time scale. The technology is well suited for operating in high radiation environments, including fusion ignition experiments. Diagnostics using hCMOS cameras are now deployed in experiments on major laser and pulsed-power ICF facilities around the world. Continued advances in microelectronics technologies will enable faster and more capable detectors well into the future. This paper reviews this detector technology with a focus on application to ICF and HEDP experiments.

Lethal complication of a rare cardiac tumor.

Cardiac tumors, especially malignant ones, are rare and diagnosis is challenging since symptoms manifest late and are often non-specific. Achieving a histological diagnosis prior to resection is also difficult because biopsies often fail to yield conclusive results. Due to the low frequency, no standard treatment protocol exists and the prognosis is poor. We present a case of a cardiac sarcoma, which was found during an autopsy performed with regard to medical malpractice, because the patient died due to a medical intervention. To report cases like this is important to gain more knowledge about possible complications regarding rare diseases.

DREAMS: deep read-level error model for sequencing data applied to low-frequency variant calling and circulating tumor DNA detection.

Circulating tumor DNA detection using next-generation sequencing (NGS) data of plasma DNA is promising for cancer identification and characterization. However, the tumor signal in the blood is often low and difficult to distinguish from errors. We present DREAMS (Deep Read-level Modelling of Sequencing-errors) for estimating error rates of individual read positions. Using DREAMS, we develop statistical methods for variant calling (DREAMS-vc) and cancer detection (DREAMS-cc). For evaluation, we generate deep targeted NGS data of matching tumor and plasma DNA from 85 colorectal cancer patients. The DREAMS approach performs better than state-of-the-art methods for variant calling and cancer detection.

Occlusive wound closure prevents prolonged wound discharge-A randomised controlled trial in patients undergoing tumour resection and endoprosthetic reconstruction of the proximal femur because of metastatic bone disease.

Prolonged wound discharge is a common postoperative complication of orthopaedic procedures and a risk factor for implant-related infection. Occlusive wound closure methods have previously been suggested to reduce or even prevent this complication. We performed a randomised controlled trial on 70 patients who underwent surgical treatment for metastatic bone disease involving the proximal femur at our centre between January 2017 and August 2018. At conclusion of the tumour resection and endoprosthetic reconstruction procedure, patients were randomised to either occlusive wound closure (n = 35), using the Dermabond Prineo-22 skin closure system, or routine wound closure with conventional skin staples (n = 35). Skin closure with occlusive wound closure resulted in a lesser degree (P < .0001) and shorter duration of postoperative wound discharge (HR 2.89 [95% CI 1.6-5.05], P < .0018). Compared with staples, surgical wounds were already dry after a mean of 3.5 days [95% CI 3.2-3.9] versus 6.1 days [95% CI 4.8-7.3] (P < .0001). Prolonged wound discharge for 7 days or more was observed in 23% of patients (n = 8) in the Staples-group but was entirely absent in the occlusive wound closure group (P < .003). This study provides strong evidence that occlusive wound closure reduces frequency, degree, and duration of wound discharge in a patient population at particularly high risk for this complication.

Sensitivity and performance of three novel quantitative assays of SARS-CoV-2 nucleoprotein in blood.

To assess if SARS-CoV-2 (COVID-19) systemic disease can be determined by available nucleoprotein assays, we compared the performance of three commercial SARS-CoV-2 nucleoprotein (N) assays in plasma. A total of 272 plasma samples collected in the period November-December 2021 were analyzed by the methods Simoa SARS CoV-2 N Protein Advantage Kit [Quanterix Simoa], Solsten SARS-CoV-2 Antigen enzyme immunosorbent assay (ELISA) [Solsten ELISA], and Elecsys SARS-CoV-2 Antigen electrochemiluminescence immunoassay [Elecsys ECLIA]. Additionally, a dilution series of inactivated virus culture was analyzed by the three assays. The SARS CoV-2 PCR-status was not known for the patients. Linear correlation in the pairwise correlation between assays as well as linearity of dilution series of inactivated virus culture was estimated by Spearman score. Sensitivity and specificity were estimated by pairwise comparison. The three assays showed poor agreement on patient samples with regards to concentration. Performance on virus culture was excellent but with different level of detection (LOD). Positive vs negative results show comparable sensitivity and specificity of Quanterix Simoa and Solsten ELISA, with a higher LOD in Elecsys ECLIA and thus lower sensitivity and high specificity. N by all tested assays can be used as a marker for systemic COVID-19 disease.

Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer.

Background & Aims: Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls. Methods: In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort. Results: Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance. Conclusion: The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls. Impact and implications: We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Combined plasma C-reactive protein, interleukin 6 and YKL-40 for detection of cancer and prognosis in patients with serious nonspecific symptoms and signs of cancer.

BACKGROUND AND METHODS: Inflammation is a hallmark of cancer and its progression. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and YKL-40 reflect inflammation, and are elevated in patients with cancer. This study investigated whether plasma CRP, IL-6 and YKL-40 had diagnostic value in 753 patients referred with nonspecific signs and symptoms of cancer to a diagnostic outpatient clinic. RESULTS: In total, 111 patients were diagnosed with cancer within 3 months and 30 after 3 months. CRP, IL-6 and YKL-40 were elevated in 44%, 60% and 45% of the cancer patients, and in 15%, 33% and 25% of the patients without cancer. Elevated levels of all three markers were associated with risk of cancer within 3 months: CRP (odds ratio (OR) 4.41, 95% confidence interval (CI) 2.86-6.81), IL-6 (OR = 2.89, 1.91-4.37) and YKL-40 (OR = 2.42, 1.59-3.66). Multivariate explorative analyses showed that increasing values were associated with the risk of getting a cancer diagnosis (continuous scale: CRP (OR = 1.28, 1.12-1.47), carcinoembryonic antigen (CEA) (OR = 1.61, 1.41-1.98), CA19-9 (OR = 1.15, 1.03-1.29), age (OR = 1.29, 1.02-1.63); dichotomized values: CRP (OR = 2.54, 1.39-4.66), CEA (OR = 4.22, 2.13-8.34), age (OR = 1.42, 1.13-1.80)). CRP had the highest diagnostic value (area under the curve = 0.69). Combined high CRP, IL-6 and YKL-40 was associated with short overall survival (HR = 3.8, 95% CI 2.5-5.9, p < 0.001). CONCLUSION: In conclusion, plasma CRP, IL-6 and YKL-40 alone or combined cannot be used to identify patients with cancer, but high levels were associated with poor prognosis. CRP may be useful to indicate whether further diagnostic evaluation is needed when patients present with nonspecific signs and symptoms of cancer.

[Barriers in mental health care for asylum seekers]. / Barrières in de ggz voor asielzoekers in hoge-inkomenslanden.

Background  Despite high prevalence of psychopathology, the use of mental health services by asylum seekers seems low. Barriers to care may play an important role in this. Aim  To explore the barriers in mental health care for adult and adolescent asylum seekers and their care providers in high-income countries. Method  A narrative literature review, based on a systematic evaluation of the current scientific literature. Results  In a narrative synthesis of the results, we identified the following six categories of barriers: lack of knowledge of the healthcare system, language barriers, discrepant beliefs and expectations of mental healthcare, lack of trust towards authority, and structural difficulties. Conclusion  Six thematic barriers were retained. Different interventions are possible to address these barriers. Further research into needs and interventions is recommended, with specific attention to the Belgian and Dutch context.

Characterization of the hardened single line of sight camera at the National Ignition Facility.

The hardened single line of sight camera has been recently characterized in preparation for its deployment on the National Ignition Facility. The latest creation based on the pulse-dilation technology leads to many new features and improvements over the previous-generation cameras to provide better quality measurements of inertial confinement fusion experiments, including during high neutron yield implosions. Here, we present the characterization data that illustrate the main performance features of this instrument, such as extended dynamic range and adjustable internal magnification, leading to improved spatial resolution.

ctDNA-guided adjuvant chemotherapy for colorectal cancer-ready for prime time?

In stage II colorectal cancer, adjuvant chemotherapy is controversial, and overtreatment is substantial due to suboptimal risk stratification. In a recent New England Journal of Medicine article reporting from a prospective randomized phase II trial, Tie and colleagues demonstrate how ctDNA-guided risk-stratification reduces the use of adjuvant chemotherapy without compromising recurrence risk.

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study.

PURPOSE: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. EXPERIMENTAL DESIGN: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test 'TriMeth'. RESULTS: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

Error Characterization and Statistical Modeling Improves Circulating Tumor DNA Detection by Droplet Digital PCR.

BACKGROUND: Droplet digital PCR (ddPCR) is a widely used and sensitive application for circulating tumor DNA (ctDNA) detection. As ctDNA is often found in low abundance, methods to separate low-signal readouts from noise are necessary. We aimed to characterize the ddPCR-generated noise and, informed by this, create a sensitive and specific ctDNA caller. METHODS: We built 2 novel complimentary ctDNA calling methods: dynamic limit of blank and concentration and assay-specific tumor load estimator (CASTLE). Both methods are informed by empirically established assay-specific noise profiles. Here, we characterized noise for 70 mutation-detecting ddPCR assays by applying each assay to 95 nonmutated samples. Using these profiles, the performance of the 2 new methods was assessed in a total of 9447 negative/positive reference samples and in 1311 real-life plasma samples from colorectal cancer patients. Lastly, performances were compared to 7 literature-established calling methods. RESULTS: For many assays, noise increased proportionally with the DNA input amount. Assays targeting transition base changes were more error-prone than transversion-targeting assays. Both our calling methods successfully accounted for the additional noise in transition assays and showed consistently high performance regardless of DNA input amount. Calling methods that were not noise-informed performed less well than noise-informed methods. CASTLE was the only calling method providing a statistical estimate of the noise-corrected mutation level and call certainty. CONCLUSIONS: Accurate error modeling is necessary for sensitive and specific ctDNA detection by ddPCR. Accounting for DNA input amounts ensures specific detection regardless of the sample-specific DNA concentration. Our results demonstrate CASTLE as a powerful tool for ctDNA calling using ddPCR.