Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “reproducibility”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMedDate not supplied

Factors influencing long-term in vivo reproducibility of QCT overtebral densitometry).

OBJECTIVE: We investigated the long-term in vivo reproducibility of quantitative CT (QCT) examinations that were conducted in conformity with a standard and well established methodology. MATERIALS AND METHODS: The long-term reproducibility in vivo of QCT vertebral densitometry was studied in 12 normal postmenopausal women (mean age 51 years), who underwent four to five examinations over the same 2 year period. RESULTS: One group of six patients demonstrated good reproducibility with a coefficient of variation (CV) of bone mineral density (BMD) of < 2.4% and were considered "good cases." The other group of six patients showed poor reproducibility with a CV of BMD of > 3.2% and were considered "problem cases." A statistical study of the technical parameters of the QCT examination was performed to determine and correct for the factors that are correlated with reproducibility errors. Analyzing uncalibrated variations in Hounsfield numbers, we found that the surrounding soft tissues such as muscle, aorta, liver, and fat were correlated in both the good and the problem cases. However, only in the good cases did we find that the Hounsfield numbers of the vertebral bodies correlated strongly with the soft tissues and with parameters characteristic of the calibration regression line. CONCLUSION: Essentially, the calibration procedure appeared to fail in some examinations of the problem cases, causing poor long-term reproducibility. This calibration failure may be related to positioning of the subject in the gantry and to variations in electrical parameters of the X-ray tube. A CV > 1% between the four slopes of calibration for the individual vertebrae measured at the same visit may indicate calibration problems and may suggest the need for repeat scanning.

Aortography↗
PubMed1996

Trunk extensor and flexor strength measured by the Cybex 6000 dynamometer. Assessment of short-term and long-term reproducibility of several strength variables.

STUDY DESIGN: Isokinetic trunk extensor and flexor strength (peak torque, total work, power acceleration time, and torque acceleration energy) at 30 degrees/sec, 120 degrees/sec, and 180 degrees/sec and isometric extensor and flexor peak torque were measured in 24 healthy women. Measurements were performed in three separate sessions at the same time of day and by the same experienced examiner. The number of days between Session 1 and Session 2 and between Session 1 and Session 3 ranged from 1 to 7 (median, 2 days) and from 23 to 48 (median, 32 days), respectively. The test results were not revealed before all sessions were completed. OBJECTIVES: To determine the intrasession, short-term, and long-term reproducibility of several trunk strength variables measured by the Cybex 6000 isokinetic dynamometer (Lumex, Inc., Ronkonkoma, NY). SUMMARY OF BACKGROUND DATA: Only few and insufficient data regarding the reproducibility of trunk strength measurements exist. Previous studies have focused on coefficients of correlation to express reproducibility. Correlations, however, are misleading and inappropriate for this purpose. The critical difference is the difference between two results that would be statistically significant when applied to a reference group in steady state. The critical difference in percentage is calculated as 2.77 X coefficient of variation (%). METHODS: Isokinetic dynamometry (Cybex 6000). Reproducibility was expressed as pooled coefficients of variation, individual coefficients of variation, and critical differences. RESULTS: Substantial between-subject variation of coefficients of variation was found for all strength variables; for example, the 80% central range for individual coefficients of variation for long-term reproducibility of extensor strength measurements at 30 degrees/sec ranged from 2.5% to 19.5%. Critical differences calculated using the pooled variances for long-term reproducibility were higher than 20% for all measures, mounting to 80% for acceleration time. CONCLUSIONS: Strength testing is of limited value in the individual subject because of considerable day-to-day variability. This finding has important clinical implications.

Adolescent↗
PubMed2002

Intraobserver reproducibility of a two-dimensional mapping of the optic nerve head perfusion.

PURPOSE: To evaluate the intraobserver reproducibility of a software designed to assess retinal blood flow with the Heidelberg Retina Flowmeter (HRF). METHODS: Ten subjects were consecutively recruited, and one eye of each patient was randomly selected for study. Blood flow measurements were analyzed by using an automatic full field perfusion image analysis (AFFPIA) program, which calculates the Doppler frequency shift and hemodynamic variables (flow, volume, and velocity) for each pixel. The resulting perfusion image is processed with respect to underexposed and overexposed pixels, saccades, and retinal vessel tree. Intraobserver reproducibility was calculated for the AFFPIA program. All the optic nerve heads were horizontally divided into three sections (superior, central, and inferior). The retinal blood flow was calculated in the superior and inferior section, and each section was further divided into three areas (temporal, nasal, and rim). The blood flow was evaluated for each area. RESULTS: When the same observer analyzed the same image five times (intraobserver intraimage reproducibility), the AFFPIA coefficient of variation ranged from 0.5% to 5% in the temporal area, from 0.1% to 5.3% in the nasal area, and from 0.5 to 28% in the rim area. When the same observer analyzed three different images of the same section once (intraobserver interimage reproducibility), the AFFPIA coefficient of variation of flow measurements ranged from 1% to 7.3% in the temporal area, from 1.5% to 10% in the nasal area, and from 2 to 30% in the rim area. CONCLUSION: Retinal blood flow measured by HRF and analyzed by AFFPIA had good intraobserver reproducibility. The reproducibility was significantly better in the temporal and nasal areas than in the rim area.

Aged↗
PubMed2005

Blood pressure dipping is reproducible in clinical practice.

OBJECTIVE: Blood pressure dipping pattern has clinical and prognostic consequences. However, reproducibility of night-time blood pressure fall during 24-h ambulatory blood pressure monitoring is considered limited. This limited reproducibility is possibly a result of inadequate day-night definitions. We retrospectively examined the reproducibility of blood pressure dipping in clinical practice, applying a method that accounts for sleep-awake states and does not rely on arbitrary day-night definitions. We also examined dipping repeatability in subjects with changing blood pressure. METHODS: Of 962 consecutive ambulatory measurements performed in our unit during a 3-year period, 100 patients (age 60+/-15) had a prior session, and were the subjects of this study. Based on patients' report we defined 'awake blood pressure' as the average of pressure recordings while the subject was awake, including night-time arousals, and 'sleep blood pressure' as the average of pressure recordings while the subject was sleeping, including afternoon naps. RESULTS: We found systolic blood pressure dipping not less reproducible than 24-h, awake- and sleep systolic blood pressure, as evaluated by both Pearson correlations (r=0.52 versus 0.5, 0.5, 0.49, respectively, P < or =0.0002 in all), and Bland-Altman repeatability. In a subgroup of 35 subjects (age 63+/-15) with at least 10 mmHg change in systolic blood pressure between the two sessions, systolic blood pressure dipping remained reproducible (r=0.45, P<0.007). CONCLUSIONS: When interpreted in a way that accounts for sleep-awake pattern, sleep-induced systolic blood pressure dipping in clinical practice is a very reproducible feature of ambulatory blood pressure monitoring, in accordance with its vital prognostic implications.

Aged↗
PubMed2006

Reproducibility of computer-aided volumetry of artificial small pulmonary nodules in ex vivo porcine lungs.

OBJECTIVE: The main purpose of this study was to investigate the reproducibility of computed tomography (CT)-based volumetric measurements of small pulmonary nodules. METHODS: We implanted 70 artificial pulmonary nodules in 5 ex vivo porcine lungs in a dedicated chest phantom. The lungs were scanned 5 times consecutively with multislice-CT (collimation 16 x 0.75 mm, slice thickness 1 mm, reconstruction increment 0.7 mm). A commercial software package was used for lesion volumetry. The authors differentiated between intrascan reproducibility, interscan reproducibility, and results from semiautomatic and postprocessed volumetry. RESULTS: Analysis of intrascan reproducibility revealed a mean variation coefficient of 6.2% for semiautomatic volumetry and of 0.7% for human adapted volumetry. For interscan reproducibility a mean variation coefficient of 9.2% and for human adapted volumetry a mean of 3.7% was detected. CONCLUSION: The presented volumetry software showed a high reproducibility that can be expected to detect nodule growth with a high degree of certainty.

Analysis of Variance↗
PubMed1993

Reproducibility of random amplified polymorphic DNA (RAPD) analysis among laboratories.

Random amplified polymorphic DNA (RAPD) analysis appears to offer a cost- and time-effective alternative to restriction fragment-length polymorphism (RFLP) analysis. However, concerns about the ability to compare RAPD results from one laboratory to another have not been addressed effectively. DNA fragments that were amplified by five primers and shown to be reproducibly polymorphic between two oat cultivars (within the Ottawa laboratory) were tested in six other laboratories in North America. Four of the six participants amplified very few or no fragments using the Ottawa protocol. These same participants were able to generate a considerable number of amplified fragments by using their own protocols. The reproducibility of results among laboratories was affected by two factors. First, different laboratories amplified different size ranges of DNA fragments, and, consequently, small and large polymorphic fragments were not always reproduced. Second, although reproducible results were obtained with four of the primers, reproducible results were not obtained with the fifth primer, using the same reaction conditions. It is suggested that if the overall temperature profiles (especially the annealing temperature) inside the tubes are identical among the laboratories, then RAPD fragments are likely to be reproducible.

Base Sequence↗
PubMed1989

Reproducibility of the skin prick test.

Reproducibility of the skin prick method of testing for allergy was studied in 20 subjects examined by four nurses. Hypodermic needles were used for pricking and the test panel included a histamine control, a diluent control, and nine allergens. The reproducibility of the method was best when the size of the weal reaction caused by an allergen was expressed as the geometric area of the weal. When the weal reaction was expressed as the ratio of the weal reaction caused by an allergen to that caused by histamine, the reproducibility of the method was decreased considerably. When the ratios were further classified into three class ratings, reproducibility was very low. The reduction in reproducibility was due to the low reproducibility of histamine reactions. According to these results, at least in epidemiological studies the weal reactions should be expressed as geometric areas. In clinical practice it might also be preferable to express prick test results as the diameters of the weals without adjusting them by histamine reactions.

Allergens↗
PubMed2005

Reproducibility of the Banff classification in subclinical kidney transplant rejection.

The Banff classification for kidney allograft pathology has proved to be reproducible, but its inter and intraobserver agreement can vary substantially among centres. The aim of this study was to evaluate Banff reproducibility of surveillance renal allograft biopsies among renal pathologists from different transplant centres. This study included 32 renal transplant patients with stable graft function. Biopsies were performed 2 and 12 months post-transplant. Histology was interpreted according to the Banff schema by three renal pathologists, and inter and intraobserver agreement were measured. The best reproducibility was obtained for the presence or absence of acute rejection (AR), with kappa values ranging from moderate (kappa = 0.47; p = 0.006) to good (kappa = 0.72; p = 0.0001). However, the agreement for 'suspicious for AR' category was poor between all observers. For scoring and grading interstitial inflammation and intimal arteritis the agreement were poor and moderate, respectively. Reproducibility for the presence or absence of chronic allograft nephropathy (CAN) was heterogeneous, ranging from poor (kappa = 0.13; p = NS) to moderate (kappa = 0.56; p = 0.007). Scoring chronic changes such as fibrous intimal thickening gave a reasonable interobserver agreement. Intraobserver reproducibility was good for presence or absence of AR, but was poor for the diagnosis of CAN. In conclusion, histologic analysis of stable renal allografts based on Banff criteria showed a good agreement for the diagnosis of AR and a reasonable kappa for CAN, but reproducibility for scoring and grading showed a substantial interobserver variation.

Adult↗
PubMed1996

Reproducibility of blood pressure and heart rate reactivity: a meta-analysis.

Reproducibilities of blood pressure and heart rate (HR) reactivity reported in studies assessing responses to the same laboratory stressors across occasions were reviewed with meta-analytic techniques. Changes in HR had the greatest reproducibility (r = .555), followed by systolic blood pressure (SBP) (.407) and diastolic blood pressure (DBP) (.348). Both SBP and HR response reproducibility was higher at shorter test-retest intervals, whereas DBP values varied unsystematically with length of test-retest interval. Older samples exhibited higher SBP and DBP reproducibility to stressors. SBP and DBP reproducibilities were better for tasks that did not make speech demands. The reliability of reactivity assessment was higher when based on three or more measurements. On the basis of available evidence, the drop in stress reproducibility, as test-retest interval increases, places limits on the viability of BP reactivity as a strong marker or risk factor for coronary heart disease.

Aging↗
PubMed2000

Reproducibility of response to programmed atrial stimulation.

The induction of atrial tachyarrhythmias (ATAs) is used to guide the medical or ablative treatment of these tachycardias. To date no information is available regarding the reproducibility of programmed atrial stimulation (PAS) induced ATA. The purpose of the study was to look for the reproducibility of PAS. Two baseline electrophysiological tests were performed in the drug-free state and within 6 months to 3 years of one another (mean 18 months) in 62 patients. Twenty-six patients had spontaneous documented ATAs (group I); 36 patients did not have spontaneous ATAs (group II). PAS used one and two extrastimuli delivered during three cycle lengths (sinus rhythm, 600 ms, 400 ms). The results were as follows. In group I, sustained (> 1 minute) ATA was induced in 23 patients on the first PAS and remained inducible in 22 patients in the second study. In three patients with noninducible ATA, PAS remained negative in only one; the reproducibility of PAS was 88%. In 17 (47%) group II patients, a sustained ATA was induced in the first study, and the ATA remained inducible in 10 patients in the second study. Nineteen other patients did not have inducible ATA on the first study, but 10 of them had an inducible ATA on the second PAS; the reproducibility of PAS was 53%. In conclusion, long-term reproducibility of PAS induced ATA in patients with spontaneous and documented ATA was good. In patients without spontaneous ATA, the reproducibility of PAS induced ATA was low and the induction of ATA in these patients should be interpreted cautiously in light of this observed variability in induced atrial arrhythmias.

Adolescent↗
PubMed1997

Reproducibility of ventricular fibrillation characteristics in patients undergoing implantable cardioverter defibrillator implantation.

INTRODUCTION: The purpose of this study was to evaluate the immediate reproducibility of local electrogram characteristics recorded during repeated episodes of induced ventricular fibrillation (VF) in patients undergoing implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: Power spectral analysis (using a fast Fourier transform algorithm) of electrograms recorded during 3 seconds of VF were analyzed in 24 patients undergoing ICD implantation using a Medtronic Transvene lead. Patients had 2 to 7 episodes of VF that were induced during defibrillation threshold testing. VF was induced by burst pacing (n = 20) or T wave shock (n = 4). Simultaneous electrograms during VF were recorded from a Medtronic Transvene lead with the following configurations: (1) a narrow spaced (12 mm) dedicated bipole used clinically for sensing; (2) a unipolar electrogram from the right ventricular coil; and (3) a widely spaced (18.3 mm) integrated bipole using the distal tip and the coil. Intraclass correlation coefficients (ICCs) were determined to examine the reproducibility of these VF characteristics among VF episodes in each patient. Recordings from both bipolar configurations had ICCs from 0.40 to 0.55, whereas unipolar recordings ICCs were below 0.40. Reproducibility was similar for dedicated and integrated recordings. CONCLUSIONS: Frequency characteristics of repeated episodes of VF induced in the same subjects show fair-to-good but not excellent reproducibility. Bipolar recordings were far more reproducible than unipolar recordings, but both bipolar configurations had similar reproducibility. These findings have implications for both the pathophysiology of induced VF and the design of VF detection algorithms.

Adult↗
PubMed2001

Reproducibility of gastric barostat studies in healthy controls and in dyspeptic patients.

OBJECTIVES: Gastric barostat studies are increasingly being performed, but their reproducibility and the most suitable study protocol have not been determined. The aim of this study was to verify the reproducibility of gastric sensitivity and accommodation testing in healthy and in dyspeptic subjects, and to compare stepwise and double random staircase distensions. METHODS: A total of 13 dyspeptic patients and 25 healthy control subjects underwent two successive studies. Sensory thresholds were assessed on a same-day/different-days protocol, using a stepwise (11/14 healthy subjects and 11/13 patients) or a double random staircase inflation (11/21 healthy subjects). In 10 healthy subjects, both methods were compared. Gastric accommodation was measured on different days in 13 patients and nine healthy subjects. Data (mean +/- SEM) were compared using the paired t test, and individual variability was expressed as the percent coefficient of variation. RESULTS: In healthy subjects, the thresholds for first perception and for discomfort were highly reproducible (p > 0.05) and the pressure thresholds showed a lower degree of variability than the volumes. Pressure thresholds quantified by stepwise showed lower variability than double random staircase inflation. In the patients, the sensory thresholds were unchanged between the sessions on the same and on different days (p > 0.05). Gastric accommodation also showed excellent reproducibility for both dyspeptic patients and healthy control subjects (p > 0.05). CONCLUSIONS: Both in dyspeptic patients and in healthy control subjects, gastric sensitivity and accommodation quantified by isobaric distensions show excellent reproducibility. Pressure and volume thresholds both are well reproducible, but the former shows less variability. Finally, the simplest stepwise protocol is better than the double random staircase to assess the gastric sensitivity to distension.

Adult↗
PubMed1997

In vitro accuracy and reproducibility of automated and conventional periodontal probes.

The aim of this study was to investigate the accuracy and reproducibility of experienced and inexperienced examiners using 3 automated periodontal probes (Florida Pocket Probe, Florida Disk Probe, Peri Probe) in comparison with 3 conventional periodontal probes (Marquis, Williams and EN-15 probes). Test blocks of aluminium had 30 holes of diameter 1.10 mm and depths ranging from 2.75 to 10.0 mm. machined with a tolerance of +/- 0.01 mm. 8 experienced examiners and 8 inexperienced examiners were selected to perform duplicate measurements on the blocks over 6 visits using each of the 6 probes. 1 automated and 1 conventional probe were used at each examination. The % accuracy and reproducibility for each of the duplicate measurements was calculated and analysed using Friedman 2-way analysis of variance and the Wilcoxon matched pairs test. On average, all probes showed high reproducibility, with the Florida Disk Probe, the Florida Pocket Probe and the Williams probe ranked best and the other 3 probes were less reproducible. On average, all probes showed a high degree of accuracy, automated probes were ranked best and were significantly better than conventional probes. Experience had little effect on reproducibility, with only the Peri Probe showing significant differences at the 5% level between the groups. Experience appeared to be more important for accuracy, as experienced examiners were more accurate than inexperienced examiners, with significant differences at the 5% level for the EN-15, Florida Disk Probe and Peri Probe. However, inexperienced examiners were significantly more accurate using the Williams probe. This in vitro study has shown that automated probes offer increased accuracy over conventional probes and the Florida Pocket and disk probes compare well with conventional probes for reproducibility.

Adult↗
PubMed2004

A method to test the reproducibility and to improve performance of computer-aided detection schemes for digitized mammograms.

The purpose of this study is to develop a new method for assessment of the reproducibility of computer-aided detection (CAD) schemes for digitized mammograms and to evaluate the possibility of using the implemented approach for improving CAD performance. Two thousand digitized mammograms (representing 500 cases) with 300 depicted verified masses were selected in the study. Series of images were generated for each digitized image by resampling after a series of slight image rotations. A CAD scheme developed in our laboratory was applied to all images to detect suspicious mass regions. We evaluated the reproducibility of the scheme using the detection sensitivity and false-positive rates for the original and resampled images. We also explored the possibility of improving CAD performance using three methods of combining results from the original and resampled images, including simple grouping, averaging output scores, and averaging output scores after grouping. The CAD scheme generated a detection score (from 0 to 1) for each identified suspicious region. A region with a detection score >0.5 was considered as positive. The CAD scheme detected 238 masses (79.3% case-based sensitivity) and identified 1093 false-positive regions (average 0.55 per image) in the original image dataset. In eleven repeated tests using original and ten sets of rotated and resampled images, the scheme detected a maximum of 271 masses and identified as many as 2359 false-positive regions. Two hundred and eighteen masses (80.4%) and 618 false-positive regions (26.2%) were detected in all 11 sets of images. Combining detection results improved reproducibility and the overall CAD performance. In the range of an average false-positive detection rate between 0.5 and 1 per image, the sensitivity of the scheme could be increased approximately 5% after averaging the scores of the regions detected in at least four images. At low false-positive rate (e.g., < or =average 0.3 per image), the grouping method alone could increase CAD sensitivity by 7%. The study demonstrated that reproducibility of a CAD scheme can be tested using a set of slightly rotated and resampled images. Because the reproducibility of true-positive detections is generally higher than that of false-positive detections, combining detection results generated from subsets of rotated and resampled images could improve both reproducibility and overall performance of CAD schemes.

Algorithms↗
PubMed1997

The accuracy and reproducibility of a global method to correct for geometric image distortion in the x-ray imaging chain.

A method to correct for geometric image distortion in the x-ray imaging chain, so-called dewarping, has been developed. A global two-dimensional polynomial model of which the degree is optimized is used. The performance of the method has been tested in a number of experiments using images of a plate with a 1 cm spaced wire grid put against the input screen of the x-ray image intensifier (14/17/27 cm). Both offline cine film and online video images were analyzed. The accuracy of the dewarp method was derived from the acquired images and from computer-simulated distorted images. The robustness and reproducibility of the dewarp method was evaluated by means of imaging the grid in various random orientations. Three parameters describing the behavior of the algorithm were considered. One is the reproducibility of the location of a dewarped position. The second parameter is the reproducibility of the distance between two adjacent dewarped positions as a measure of the reproducibility of the size of an object under investigation. The third parameter is the reproducibility of the pixel size in the plane of the calibration plate. The major results are: the reproducibility of the location of a dewarped position was 0.01-0.04 mm for cine film and 0.04-0.07 mm for video images. The coefficient of variation of the distance between two dewarped positions was 0.04%-0.11% for cine film and 0.15%-0.18% for video images. The dewarp algorithm turned out to be fast and accurate and the distortion was removed over the whole image field down to a low random residual level. It was found that a random orientation of the grid did not affect the assessment of the distortion nor its correction. The dewarp method proved to be intrinsically robust and highly reliable. Time instability of the imaging chain was the main source of variability in the dewarp results.

Algorithms↗
PubMed1990

Reproducibility of API Staph-Ident system identifications of coagulase-negative staphylococci isolated from blood.

Fifty-five isolates of coagulase-negative staphylococci from blood were identified four times each by using the API Staph-Ident (API-SI) system to determine the identification reproducibility of the system. Identifications were determined by using both Version 1 and Version 2 of the API-SI Profile Index. The 75 to 100% reproducibility levels, including reproducible nonidentifications, were 98.2% for Version 1 and 96.4% for Version 2. Version 1 gave an identification for 92.5% of the isolates with a 75 to 100% reproducibility, while Version 2 gave an identification for 100% of the isolates with a 75 to 100% reproducibility. The reproducibility of the API-SI identifications of coagulase-negative staphylococci from blood was good.

Bacteriological Techniques↗
PubMed1990

Reproducibility and indices of discriminatory power of microbial typing methods.

When microbial strain-typing methods are compared, the most important characteristics are typeability, reproducibility, and discriminatory power. While typeability and reproducibility can be presented as numerical values, indices of discriminatory power have only recently been described. This paper examines the relationship between reproducibility and indices of discriminatory power. In an individual typing method, an inverse relationship between reproducibility and discriminatory power appears as the number of test differences required in order to distinguish between strains is increased. A method of standardizing the discriminatory power of a typing method to a predetermined reproducibility is presented. In this way the discriminatory powers of different typing methods can be compared while being standardized for the effect of reproducibility.

Bacterial Typing Techniques↗
PubMed2004

Measurement reproducibility in the early stages of biomarker development.

Biomarker discovery and development requires measurement reproducibility studies in addition to case-control studies. Parallel pursuit of reproducibility studies is especially important for emerging technologies such as protein biomarkers based on time-of-flight mass spectrometry, the case considered in this paper. For parallel studies, a way to improve reproducibility prior to identification of protein species is necessary. One approach is use of functional principal components analysis (PCA) as the basis for assessing measurement reproducibility. Reproducibility studies involve repeated measurement of a reference material such as a human serum standard. Measurement in our example is by SELDI-TOF (surface-enhanced laser desorption and ionization time-of-flight) mass spectrometry. Reproducibility is defined in reference to a source of variation, which in our example is associated with a type of commercially available protein biochip. We obtained spectra for 8 spots on each 11 chips. Two spectra are generally more alike when obtained from the same chip rather than different chips. Thus, our experiment indicates potential improvements from reducing variation in chip manufacture and chip handling during measurement. Our analysis involves careful registration of the spectra and characterization of the spectral differences. As shown by our example, a metrological analysis may enhance case-control studies by guiding optimization of the measurements underlying the biomarker.

Biomarkers↗