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PubMed2025

MRDagent: iterative and adaptive parameter optimization for stable ctDNA-based MRD detection in heterogeneous samples.

MOTIVATION: Minimal residual disease (MRD) as critical biomarker for cancer prognosis and management plays a crucial role in improving patient outcomes. However, detecting MRD via next-generation sequencing-based circulating tumor DNA variant calling remains unstable due to the extremely low variant allele frequency and significant inter- and intra-sample heterogeneity. Although parameter optimization can theoretically enhance the detection performance of variants, achieving stable MRD detection remains challenging due to three key factors: (i) the necessity for individualized parameter tuning across numerous heterogeneous genomic intervals within each sample, (ii) the tightly interdependent parameter requirements across different stages of variant detection workflows, and (iii) the limitations of current automated parameter optimization methods. RESULTS: In this study, we propose MRDagent, a novel variant detection tool designed specifically for MRD detection. MRDagent incorporates an iterative and self-adaptive optimization framework capable of handling unknown objectives, varying constraints, and highly coupled parameters across stages. A key innovation of MRDagent is the integration of a convolutional neural network-based meta-model, trained on historical data to enable rapid parameter prediction. This significantly enhances computational efficiency and generalization performance. Extensive evaluations on simulated and real-world datasets demonstrate MRDagent's superior and stable performance, providing an efficient, reliable solution for MRD detection in clinical and high-throughput research applications. AVAILABILITY AND IMPLEMENTATION: MRDagent is freely available at https://github.com/aAT0047/MRDagent.git. The corresponding dataset and software archive are available at Zenodo: https://doi.org/10.5281/zenodo.15458496.

Circulating Tumor DNA↗
PubMed2005

Adaptive design and estimation in randomized clinical trials with correlated observations.

Clinical trial designs involving correlated data often arise in biomedical research. The intracluster correlation needs to be taken into account to ensure the validity of sample size and power calculations. In contrast to the fixed-sample designs, we propose a flexible trial design with adaptive monitoring and inference procedures. The total sample size is not predetermined, but adaptively re-estimated using observed data via a systematic mechanism. The final inference is based on a weighted average of the block-wise test statistics using generalized estimating equations, where the weight for each block depends on cumulated data from the ongoing trial. When there are no significant treatment effects, the devised stopping rule allows for early termination of the trial and acceptance of the null hypothesis. The proposed design updates information regarding both the effect size and within-cluster correlation based on the cumulated data in order to achieve a desired power. Estimation of the parameter of interest and its confidence interval are proposed. We conduct simulation studies to examine the operating characteristics and illustrate the proposed method with an example.

Biometry↗
PubMed2003

Reliable real-time spike discrimination during microstimulation.

A fundamental technical hurdle in systems neurophysiology has been to record the activity of individual neurons in situ while using microstimulation to activate inputs or outputs. Stimulation artifact at the recording electrode has largely limited the usefulness of combined stimulating and recording to using single stimulation pulses or to presenting brief trains of pulses to look for transient responses. We have developed an adaptive filter that in real time allows continuous extracellular isolation of individual neural spikes during sustained experimental microstimulation. Using signal detection analysis we now quantifiably demonstrate the reliability of spike recovery from stimulus-corrupted records. Recordings were made from the regular firing of action potentials from the oculomotor or trochlear nuclei of two macaque monkeys while stimulating at a variety of locations. We found that the adaptive filter technique gave a projected error rate of <1 in 10(4) and the detection index, d', was significantly better than two other methods tested: a 4-parameter 'window discriminator' technique and the sample-and-hold technique. This adaptive technique should generalize to any recording situation where a stereotyped, triggered transient might obscure a neural event and will significantly advance our knowledge in areas of electrophysiology where the experimental design requires prolonged microstimulation.

Action Potentials↗
PubMed1993

[Randomized comparison of transabdominal, transcervical chorionic villi sampling and amniocentesis].

The transabdominal chorionic villus sampling method was compared with the transcervical route and second trimester amniocentesis in a 3-winged randomised trial. Examination of 45 epidemiological variables showed the three procedure groups to be comparable at enrollment. In 3079 women at low genetic risk, we compared transabdominal with transcervical chorionic villus sampling and amniocentesis. The total fetal loss was 10.9%, 6.3% and 6.4% in the transcervical, transabdominal chorionic villus sampling groups and the amniocentesis group, respectively (p < 0.001). The two CVS procedures were compared in 2882 low and high genetic risk women with cytogenetically normal fetuses. Rates of unintended post-procedure loss were 3.7% and 7.7% for transabdominal CVS and transcervical CVS, respectively (p < 0.001), difference in rates 4.0%, 95% C.I. +2.3% to +5.8%. By a priori ultrasound scanning, more transcervical than transabdominal procedures (p < 0.001) were considered to be inaccessible for sampling. Our data indicate that transabdominal allows freer access to the placental site than transcervical sampling and is easier to adapt to than transcervical CVS. Women run comparable risks with transabdominal CVS and amniocentesis. Given the results of our study, transabdominal procedures remain the first choice for prenatal diagnosis and, since in our hands transcervical sampling entails an increased fetal risk, we have abandoned transcervical CVS in our two study centres.

Adult↗
PubMed2005

Biodegradation rates in adapted surface water can be assessed following a preadaptation period with semi-continuous operation.

The paper presents a semi-continuous preexposure procedure (SCEP) for use with surface water batch simulation biodegradability tests at low test substance concentrations (0.1-100 microg/l). Simple one step batch tests are normally used first of all for determining "initial rates" characteristic of the water as sampled, as by contrast to "adapted" rates obtained as a result of exposure of the microbial community to the test compound. The aim of the SCEP is to facilitate this adaptation and to become able to estimate reproducible "adapted rates" representing a steady state situation. This is accomplished by maintaining the microbial diversity and a supply of test substance and natural substrates. Conducting a SCEP involves regular renewal of part (e.g. one third) of the test suspension (e.g. every two weeks) adding freshly collected natural water with test compound of the initial concentration. An example study was performed with aniline, 4-nitrophenol, 2,4-dichlorophenoxyacetic acid, 4-chloroaniline, and water from the urban river Mølleå. Following preadaptation lag phases were considerably reduced and much more reproducible than obtained with simple batch tests. In tests at 100 microg/l lag phases for aniline decreased from 5.2 to <1 day, 4-nitrophenol from 10 to <1 day, 2,4-dichlorophenoxyacetic acid from 24 to <1 day, and 4-chloroaniline from 88 to 9 days, respectively. Adapted rates obtained with the SCECP were roughly the same as final rates in simple batch tests with successful adaptation. The adapted rate constant is perceived as an inherent characteristic of the test compound at a specific concentration and under environmental influence (temperature, natural substrates, etc.) but with no simple links back to the original microbial population. By contrast, the initial rates in one step batch tests are determined also by the microbial population initially present in the water sampled.

Automation↗
PubMed2000

New HPLC evidence on endogenous tauret in retina and pigment epithelium.

This investigation was improve the separation for tauret (retinylidene taurine) and to compare its content in the retina under dark and light adaptation. To prevent tauret hydrolysis, retinal samples were quickly frozen and lyophilized. Methanol extracts of dried retina and pigment epithelium from both dark- or light-adapted frogs, Rana ridibunda, were injected onto HPLC. Synthetic standard tauret appeared at 4.7 min after the solvent front. At the same time, an endogenous substance was eluted from the mixed retinal and pigment epithelial samples. The UV spectra of this endogenous compound matched with the spectra of synthetic tauret obtained under identical conditions, with lambda(max) = 446 nm at peak. We conclude that the HPLC system used permitted full separation of tauret from the methanol extracts of the retina and pigment epithelium. TLC and further HPLC analysis have shown that tauret quantities were several times higher in the retina and pigment epithelium of the frogs adapted to dark compared with those light-adapted (about 4 h under 1000 1x illumination). Tauret based vitamin A transport is probably involved in other systems as well, where along with its other known beneficial effects taurine probably is necessary to facilitate vitamin A transport.

Animals↗
PubMed1998

Continuous blood withdrawal as a rapid screening method for determining clearance of oral bioavailability in rats.

PURPOSE: To develop a methodology for continuous blood withdrawal in rats suitable for drug discovery screening purposes and perform limited validation studies with a series of test compounds. METHODS: A reliable methodology for continuous blood withdrawal in rats was developed. The method is dependent on continuous heparin infusion during withdrawal and the minimization of constrictive, thrombogenic sites. Plasma drug concentrations from either intermittent sampling or continuous withdrawal experiments were determined with HPLC analysis. RESULTS: The continuous withdrawal method was successfully adapted to rats such that blood samples could be reliably collected over a 6-hr experiment. The clearance and oral bioavailability values for theophylline, atenolol, propranolol, warfarin, BMS-182874 and BMS-A were determined from continuous withdrawal or intermittent sampling experiments. The results from the two methods were comparable, with each compound reliably placed in the same low, medium or high category based on clearance or oral bioavailability characteristics. CONCLUSIONS: The continuous withdrawal method proved to be a viable alternative to the classic intermittent sampling technique. The method should prove useful in drug discovery screening, where the evaluation of large numbers of compounds for systemic clearance or oral bioavailability is often necessary.

Administration, Oral↗
PubMed2002

Nondestructive near-infrared spectroscopic measurement of multiple analytes in undiluted samples of serum-based cell culture media.

An adaptive calibration procedure is used to build selective multivariate calibration models for the measurement of glucose, lactate, glutamine, and ammonia in undiluted serum-based cell culture media. This adaptive procedure removes metabolism-induced covariance between these analytes in a series of calibration samples collected during the cultivation of PC-3 human prostate cancer cells. Partial least-squares calibration models are generated from single-beam near-infrared (NIR) spectra collected over the 4800- to 4200-cm(-1) combination spectral range. Calibration models were generated with both the full spectral range and optimized spectral ranges. In both cases, the number of model factors was optimized and model validity was determined by comparing analyte concentrations predicted from a series of independent and unaltered samples that were obtained during a subsequent cultivation of the PC-3 cells. Similar analytical performance was achieved with fewer model factors when the optimized spectral range was used. The lowest standard errors of prediction were 0.82, 0.94, 0.55, and 0.76 mM for glucose, lactate, glutamine, and ammonia, respectively. Different spectral ranges were optimal for each analyte and the optimized spectral range coincided with the distinguishing spectral features of the analyte. The results of this study demonstrate that NIR spectroscopy can be used effectively in the off-line measurement of important nutrients (glucose and glutamine) and byproducts (lactate and ammonia) in a serum-based animal cell culture medium.

Algorithms↗
PubMed1999

Development of a 96-well enzyme-linked solid-phase assay for beta-glucanase and xylanase.

An enzyme-linked sorbent assay (ELSA) for estimating beta-glucanase activity was developed on the basis of the use of biotinylated beta-glucan as a solid-phase substrate. The assay involves the coating of titer plate wells with biotinylated beta-glucan, the partial hydrolysis of this substrate with beta-glucanase, the reaction of the biotin from the unhydrolyzed substrate with an alkaline phosphatase-streptavidin complex, and quantitation of the remaining beta-glucan using alkaline phosphatase. The activity of the bound indicator enzyme, alkaline phosphatase, is proportionally related to the beta-glucanase activity in the sample. The ELSA is simple, can be readily adapted to the routine assay of a large number of samples (as many as 200 per person/day), and has good precision (CV = 4.0-6.4%) and high sensitivity (detects as low as 0. 001 mU of beta-glucanase/assay). A similar assay was developed for xylanase using biotinylated arabinoxylan. The ELSA provides a simple and sensitive estimate of beta-glucanase and xylanase activity.

Biotinylation↗
PubMed2000

Theoretical investigation of the interrelationships between stationary and personal sampling in exposure estimation.

In exposure estimation, personal sampling is the method of choice as it is a nearby representative of the contaminant concentration in the breathing zone. Due to the versatility of the stationary sampling in obtaining much higher sensitivity, in its adaptability to telemetering observations, it may also be an attractive sampling method for many circumstances. However, the two sampling methods differ in many theoretically important ways that go beyond the obvious differences. The theoretical investigation of the stationary and personal sampling methods vis-à-vis sampling for exposure estimation shows that the area sampling can be used to represent personal sampling under restricted conditions. Under the restricted conditions, an area of concentration within specified bounds may be determined in relation to a reasonably well-defined source. The extension of the theory to multiple or ill-defined sources pose potential complications that may be intractable through a theoretical analysis. These limitations and restrictions are inherent to the underlying premises of the two methods; therefore they are not amenable to easy correction. Even though these restrictions may suggest only a limited role for area sampling in exposure assessment, the theory shown also suggests areas of further applied and theoretical research to extend the proper use of area sampling in exposure assessment.

Environmental Exposure↗
PubMed1977

Subjective adaptation to loss of the work role: a longitudinal study.

Both social psychologists and social gerontologists have expressed considerable interest in adaptation to the loss of central life roles. The relationship between retirement and morale, where morale is viewed as an indicator of adaptation, is an example of research within this theoretical framework. In this study, longitudinal data for a select sample of 58 male subjects were used to examine intensively the process of adaptation to retirement. The strongest finding was evidence of high levels of adaptation in the sample as reflected in the overwhelming stability of morale over time. Multiple regression analysis indicated that social resources, particularly marital status and socioeconomic status, condition the relationship between adaptation and retirement. In summary, our analysis supports current suggestions that retirement be viewed as an event which occasions a complex social process of adaptation conditioned by a variety of resource and temporal variables.

Adaptation, Psychological↗
PubMed2004

Adolescents with Turkish background in Norway and Sweden: a comparative study of their psychological adaptation.

Using a questionnaire survey, this study compared psychological adaptation (self-esteem, life satisfaction, and mental health problems) of Turkish adolescents in Norway and Sweden, and examined to what extent ethnic and majority identities, acculturation strategies, and perceived discrimination accounted for adaptation among Turkish adolescents. The samples consisted of 407 Turks (111 in Norway and 296 in Sweden) with a mean age of 15.2 years and 433 host adolescents (207 in Norway, 226 in Sweden) with a mean age of 15.6 years. Turks in Norway reported poorer psychological adaptation than Turks in Sweden. Predictors of good adaptation were Turkish identity and integration, whereas poor adaptation was related to marginalization and perceived discrimination. The results indicated that the poorer adaptation of Turks in Norway compared to that of Turks in Sweden could be due to lower degree of Turkish identity and higher degree of perceived discrimination.

Acculturation↗
PubMed2006

Dietary quality and associated factors among adults living in the state of São Paulo, Brazil.

This study sought to analyze dietary quality and associated factors among adults living in regions of the State of São Paulo, Brazil. It was a cross-sectional population-based study of a sample of 3,454 adults ages 20 years and over who were included in the Household Health Survey. Dietary intake was measured by means of the 24-hour recall method, and dietary quality was assessed by means of the Healthy Eating Index (HEI), adapted to local realities. Probabilistic samples were obtained via multistage cluster samples from four regions in the State of São Paulo. Linear regression analyses were performed to evaluate the relationships between the HEI and the demographic, socioeconomic, and lifestyle variables. Among the individuals assessed, 5% had a good diet, 74% a diet that needed some degree of improvement, and 21% a poor diet. The means for HEI components were lowest for vegetables, fruits, and dairy products. The highest HEI scores were obtained by individuals who were nonsmokers, practiced physical activity, were retired, lived in houses or apartments, and had adequate living conditions surrounding them. In the multiple regression analysis, the variables of numbers of consumer durable goods, schooling of the head of the family, energy intake, and age had a positive association with the HEI. However, the association was inverse for the variables of smoking and body mass index. Higher dietary quality is associated with higher income, higher schooling level, better nutritional status, and being a nonsmoker. Knowledge of these factors is important for implementing programs for preventive nutrition or intervention.

Adult↗
PubMed2000

Nurse stress associated with aggression in people with dementia: its relationship to hardiness, cognitive appraisal and coping.

This study examined the relationship between aggressive behaviour displayed by people with dementia and nurse stress. This was achieved by re-examining the relationships between the hardy personality (total hardiness), primary appraisal (challenge and threat appraisal), secondary appraisal (coping options available), and coping methods (action and palliative coping) from the perspective of nurse stress in response to aggressive behaviour displayed by people with dementia. One hundred and two nurses from 15 nursing homes and hostels were sampled by way of a questionnaire. Hierarchical regression was performed to analyse the strong hypothesized relationships between the variables examined. Results indicated that resident aggression was significantly related to an increase in nurse stress (M=34.79, SD=7.93). Of the variables examined, only threat appraisal was significantly related to nurse stress (beta[94]=0.48, P < 0.05). Perceiving the possibility of aggressive behaviour by the resident as threatening was found related to a high stress level in nurses sampled.

Adaptation, Psychological↗
PubMed2002

Sense of coherence and smoking in a sample of abused women.

The Antonovsky thesis (1987) of the relationship between sense of coherence and smoking, a health-related behavior, was investigated in a group of 83 raped and battered women. Analysis indicated that the simple model of "sense of coherence-health-related behavior' relationship (the higher the sense of coherence or its components the healthier behaviors, i.e., lower rates of smoking) cannot be accepted for this sample.

Adaptation, Psychological↗
PubMed1990

Automated blood-sample handling in the clinical laboratory.

The only significant advances in blood-taking in 25 years have been the disposable needle and evacuated blood-drawing tube. With the exception of a few isolated barcode experiments, most sample-tracking is performed through handwritten or computer-printed labels. Attempts to reduce the hazards of centrifugation have resulted in air-tight lids or chambers, the use of which is time-consuming and cumbersome. Most commonly used clinical analyzers require serum or plasma, distributed into specialized containers, unique to that analyzer. Aliquots for different tests are prepared by handpouring or pipetting. Moderate to large clinical laboratories perform so many different tests that even multi-analyzers performing multiple analyses on a single sample may account for only a portion of all tests ordered for a patient. Thus several aliquots of each specimen are usually required. We have developed a proprietary serial centrifuge and blood-collection tube suitable for incorporation into an automated or robotic sample-handling system. The system we propose is (a) safe--avoids or prevents biological danger to the many "handlers" of blood; (b) small--minimizes the amount of sample taken and space required to adapt to the needs of satellite and mobile testing, and direct interfacing with analyzers; (c) serial--permits each sample to be treated according to its own "merits," optimizes throughput, and facilitates flexible automation; and (d) smart--ensures quality results through monitoring and intelligent control of patient identification, sample characteristics, and separation process.

Blood Specimen Collection↗
PubMed1992

Associated luteinizing hormone-releasing hormone and luteinizing hormone secretion in ovariectomized gilts.

The secretion of luteinizing hormone-releasing hormone (LHRH) and its temporal association with pulses of luteinizing hormone (LH) was examined in ovariectomized prepuberal gilts. Push-pull cannulae (PPC) were implanted within the anterior pituitary gland and LHRH was quantified from 10 min (200 microliters) perfusate samples. Serum LH concentrations were determined from jugular vein blood obtained at the midpoint of perfusate collection. Initial studies without collection of blood samples, indicated that LHRH secretion in the ovariectomized gilt was pulsatile with pulses comprised of one to three samples. However, most pulses were probably of rapid onset and short duration, since they comprised only one sample. Greater LHRH pulse amplitudes were associated with PPC locations within medial regions of the anterior pituitary close to the median eminence. In studies which involved blood collection, LH secretion was not affected by push-pull perfusion of the anterior pituitary gland in most gilts, however, adaptation of pigs to the sampling procedures was essential for prolonged sampling. There was a close temporal relationship between perfusate LHRH pulses and serum LH pulses with LHRH pulses occurring coincident or one sample preceding serum LH pulses. There were occasional LHRH pulses without LH pulses and LH pulses without detectable LHRH pulses. These results provide direct evidence that pulsatile LHRH secretion is associated with pulsatile LH secretion in ovariectomized gilts. In addition, PPC perfusion of the anterior pituitary is a viable procedure for assessing hypothalamic hypophyseal neurohormone relationships.

Animals↗