An improved procedure for low-dose carcinogenic risk assessment from animal data

An improved procedure is presented for estimating low-dose risks from dichotomous animal data based upon the multistage model of cancer. The procedure embodies both a proper fit to experimental data and an assumption of approximate linearity of the dose-response curve in the low-dose range. Because of this low-dose-linearity the procedure may be also considered to be a generalized method for linear extrapolation which uses all of the data. The extrapolation method is different from an earlier method based upon the multistage model in that an improved procedure is put forward for calculating statistical confidence limits and a recommendation is made for the integration of several data sets in the calculation of risk levels.     

Cumulated activities determined from biodistribution data in pregnant rats ranging from 13 to 21 days gestation. I. Tc-99m pertechnetate

Cumulated activity estimates for Tc-99m pertechnetate were determined using biodistribution data from pregnant and nonpregnant rats. The pregnant rats were studied at 13, 15, 17, 19, and 21 days gestation. The results indicate that maternal organ cumulated activities are not a simple function of gestational age. The organs into which Tc-99m pertechnetate enters through passive diffusion follow the pattern established by the blood, generally resulting in an increase from the 13th through the 17th day with a decrease on the 19th and 21st day. The organs dominated by active transport follow unique and different patterns. The fetal cumulated activity estimates increased exponentially with gestational age and the placental estimates increased linearly.     

Bootstrap estimation of confidence intervals on mutation rate ratios

The fluctuation test is a useful tool for estimating the mutation rate of cells. However, statistical methods for comparing mutation rate estimates between different strains or conditions have not yet been fully developed. Methods exist for placing confidence intervals on estimates of the number of mutational events in cultures for a given strain and set of conditions, but placing confidence intervals on mutation rate is complicated by differences in the final number of cells in culture between parallel cultures. Additionally, confidence intervals on individual mutation rate estimates are not always the most useful statistical tool when comparing two or more different strains or conditions. We present a bootstrap method for estimating confidence intervals on the quotient of two mutation rates determined from two fluctuation test experiments using experimental and control strains or conditions. We use Monte Carlo simulations to validate this method over a wide range of mutation rates and for empirically measured variation in the estimates of final number of cells in culture. Furthermore, we provide the computational tools to implement the bootstrap method described here on experimental fluctuation test data and to evaluate this method for experimental parameters other than those considered herein.     

On the comparison of FROC curves in mammography CAD systems

We present a novel method for assessing the performance of computer-aided detection systems on unseen cases at a given sensitivity level. The sampling error introduced when training the system on a limited data set is captured as the uncertainty in determining the system threshold that would yield a certain predetermined sensitivity on unseen data sets. By estimating the distribution of system thresholds, we construct a confidence interval for the expected number of false positive markings per image at a given sensitivity. We present two alternative procedures for estimating the probability density functions needed for the construction of the confidence interval. The first is based on the common assumption of Poisson distributed number of false positive markings per image. This procedure also relies on the assumption of independence between false positives and sensitivity, an assumption that can be relaxed with the second procedure, which is nonparametric. The second procedure uses the bootstrap applied to the data generated in the leave-one-out construction of the FROC curve, and is a fast and robust way of obtaining the desired confidence interval. Standard FROC curve analysis does not account for the uncertainty in setting the system threshold, so this method should allow for a more fair comparison of different systems. The resulting confidence intervals are surprisingly wide. For our system a conventional FROC curve analysis yields 0.47 false positive markings per image at 90% sensitivity. The 90% confidence interval for the number of false positive markings per image is (0.28, 1.02) with the parametric procedure and (0.27, 1.04) with the nonparametric bootstrap. Due to its computational simplicity and its allowing more fair comparisons between systems, we propose this method as a complement to the traditionally presented FROC curves.     

Theoretical dosimetry estimations for radioisotopes produced by proton-induced reactions on natural and enriched molybdenum targets

This study presents a summary of the dosimetry calculations performed for three technetium agents most commonly used in nuclear medicine diagnostic studies, namely sestamibi?, phosphonates and pertechnetate, labeled with cyclotron-produced technetium. Calculated patient doses were compared to those that would be delivered by the same radiotracers labeled with technetium obtained from a generator produced in a reactor. The main difference is that technetium from a generator is pure, i.e. contains only (99m)Tc and its decay product (99g)Tc, while in a cyclotron a large number of other stable and radioactive isotopes are created. In our calculations only technetium radioisotopes (ground and isomeric states) were considered as they will be included in the radiotracer labeling process and will contribute to the patient dose. Other elements should be removed by chemical purification. These dose estimates are based on our theoretical calculations of the proton-induced reaction cross sections and radioisotope production yields. Thick targets of enriched (three different compositions) and natural molybdenum, and three initial beam energies (16, 19 and 24 MeV) were considered for irradiation times of 3, 6 and 12 h with a beam current of 200 μA. The doses were calculated for injection times corresponding to 0, 2, 8, 12 and 24 h after the end of beam.     

Detection of medullary carcinoma of thyroid, with liver metastasis, using 99mTc DMSA(V) scintigraphy

A sixty year old female referred for thyroid and liver scintigraphy had a clinical history of progressive swelling in the neck with hepatomegaly. A large cold area was detected in the right thyroid lobe using 99mTc pertechnetate and in the right lobe of liver using 99mTc phytate. Subsequent whole body scan with 99mTC DMSA(V) showed avid tracer uptake in right lobe of thyroid and liver. Aspiration cytology of thyroid and liver showed medullary carcinoma of thyroid with its metastasis in liver. Histopathology following thyroidectomy confirmed the diagnosis. Thus 99mTc pentavalent DMSA contributes specificity to diagnose medullary carcinoma of thyroid and metastatic lesions.     

Dilution assay statistics.

A parametric method of statistical analysis for dilution assays is developed in detail from first principles of probability and statistics. The method is based on a simple product binomial model for the experiment and produces an estimate for the concentration of target entities, a confidence interval for this concentration, and an indicator of the quality of the assay called the p value for goodness of fit. The procedure is illustrated with data from a virologic quantitative micrococulture assay used to quantify free human immunodeficiency virus in clinical trials. The merits of the procedure versus those of nonparametric methods of estimating the dilution inducing a 50% response rate are discussed. Advantages of the proposed approach include plausibility of the underlying assumptions, ability to assess plausibility of specific experimental outcomes through their likelihood, and plausibility of confidence intervals.     

Trilinear Modeling of Event-Related Potentials

This paper describes a method for estimating a set of spatial components (brain maps) and temporal components (waveforms) of brain potentials. These components play the role of bases of a coordinate system, in the sense that the brain potentials of any subject can be represented as superpositions of these components. The representation is unique given the spatial and temporal components, and this decomposition is particularly appealing for comparing the brain potentials of different subjects (say alcoholics and controls). It can also be used for single trial modeling, clinical classification of patients, and data filtering. The method is based on the topographic component model (TCM, Möcks 1988) which models brain potentials in a trilinear form. We extend the TCM in two aspects. First, the diagonal amplitude matrix is replaced by a general loading matrix based on some neurophysiological considerations. Secondly, the number of spatial components and the number of temporal components can be different. The spatial components and temporal components are obtained respectively by performing singular value decomposition (SVD). This method is illustrated with visual P3 data.     

Estimation of Cronbach's alpha coefficient in the context of item response theory

Cronbach's alpha coefficient is an index of reliability for the total score of a set of measurements. The alpha takes a value of 1.0 when the total score variance is perfectly attributable to the common factors running through the test items. In this research, a method of estimating Cronbach's coefficient alpha is proposed for the case where the parameters of dichotomous item response model are known and the ability distribution of subjects is given. In addition, the case of polytomous response model where the item parameters are estimated by graded response model (Samejima, 1969) is also considered, and a method of estimating the alpha coefficient is proposed for that case.     

Predicting the spatiotemporal expression of local and referred acute muscle pain in individual subjects

While current data suggest that all referred pain derives from common mechanisms of central sensitisation, there is a paucity of data directly comparing referral in different limbs. Does a common mechanism result in similar precepts of referral from similar stimuli in different limbs? We tested the hypothesis that, in a given subject, the incidence, intensity and spatiotemporal expression of referred pain are similar during the muscle pain induced by bolus intramuscular injection of hypertonic saline into flexor carpi radialis (FCR) and tibialis anterior (TA). We also tested the hypothesis that an increase in stimulus intensity causes a parallel increase in the incidence and intensity of local and referred pain, by comparing the responses to 5 and 10 % hypertonic saline in two groups of subjects. 29 subjects mapped areas of local and referred pain, rating intensities on a visual analogue scale every 30 s until the cessation of pain. Following an injection of 5 % hypertonic saline into TA, 86 % of subjects who had previously reported referred pain (or its absence) in the hand during FCR pain reported referred pain (or its absence) in the foot. Following an injection of the 10 % solution, 67 % of subjects reported a pattern in the lower limb that was the same as that seen in the upper limb. We conclude that the expression of referred pain is largely consistent in widely separated limb segments in individual subjects and is largely dependent on inter-subject differences. This may have implications for the development of chronic pain following an acute episode of pain.     

Confidence limits for the parameter estimation in the dipole localization method on the basis of spatial correlation of background EEG

Summary A new residual function in the inverse problem of equivalent dipole localization methods is proposed which is based on the spatial correlation of the background EEG. This residual has the advantage that it allows the calculation of confidence limits for dipole model parameters. The method was applied to VEP data, and it was studied how the localization precision depends on the recording time of the EEG. It was found that the tangential position of an equivalent dipole can be located at 99% confidence in a region of the order 7 × 7mm for a head radius of 10cm, while the 99% confidence interval of the depth estimate is approximately 1cm, with a recording time of 20 minutes. It was also observed that an EEG recording time of more than 10–15 minutes is needed to obtain stable localization precision estimates.     

Irregular field calculation on the central beam axis of photon beams using sector-integration

A method is proposed for calculation of irregular field factors on the central beam axis and homogeneous medium for x-ray beams. The irregular field factor is introduced as the ratio of the output of a field with and without blocks on the central beam axis. The algorithm is based on the sector-integration method and the circular field quantities are calculated from in-phantom measurements. These circular field quantities are the output per beam monitor unit for circular fields defined by a hypothetical secondary collimator and reduced to a circular field by blocking. A derivation of the sector-integration equation is given from first principles. As it is shown, the circular field quantities are evaluated from data measured for rectangular, block shaped fields. Such quantities contain all beam components, including photons scattered from the blocks, the block tray, and photons scattered in the phantom. Consequently, the so called primary and secondary beam components are readily incorporated in this approach. Once the circular field quantities have been determined from rectangular field data, the irregular field factors for other geometry can be calculated. Irregular field factors for square, rectangular and circular block-shaped fields were calculated for 6 MV photon beams and compared with measured values. The results agree within 0.7%, even for heavy blocked field cases, i.e., a 40 x 40 cm2 collimator field blocked to a 5 x 5 cm2 field. The method was tested for a particular source to surface distance, depth, phantom composition, and source to block distance. Calculation of irregular field factors in another set up conditions requires the measurement of the appropriate input data.     

Oesophageal transit of a radionuclide solid bolus in normals

The purpose of this study was to evaluate the physiological transit pattern of a compact bolus through the oesophagus in normal subjects. A standard gelatine bolus labelled with 99mTechnetium pertechnetate was swallowed in the erect and the supine positions and traced by a gamma-camera in 20 subjects. In the erect position, the mean overall transit time was 5.5 +/- 1.1 s (SD) which differed significantly (P less than 0.001) from the longer mean overall transit time of 6.9 +/- 1.4 s (SD) in the supine position. The transit patterns differed between erect and supine positions. In the erect position, the bolus travelled at a constant velocity until the most distal part of the oesophagus where a slight retardation of the velocity occurred, whilst in the supine position, a uniform retardation of the velocity was seen which was slightly accentuated in the most distal part. The present data provide a basis for the evaluation of studies on the bolus transport in patients with suspected oesophageal dysfunction.     

Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation

Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel?, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 12 weeks (group B). Corticosteroids (if present at study entry) were kept constant for the initial 4 weeks of therapy and then tapered as tolerated. Thirty-one of 34 (91%) subjects were evaluable for response, and 10 (32%) met primary response criteria. There was no difference in response based on the duration of treatment (29% group A versus 35% group B; P = .99), the presence of RLD or OLD (33% versus 32%; P = .73), or the severity of pulmonary disease at study onset. Estimated 5-year overall survival rates following therapy were 61% (95% confidence interval, 46%-80%) for all subjects and 90% (95% confidence level, 73%-100%) for the 10 who met the primary response criteria. Five-year survival estimates for subjects treated with RLD was 44%, compared with 67% for those treated for OLD (P = .19). Etanercept was well tolerated, with no bacteremia or viremia observed. Pathogens were noted on posttherapy bronchoalveolar lavage in two cases. These data support the development of expanded clinical trials to study etanercept as a therapeutic agent for subacute lung injury after allogeneic stem cell transplantation.     

Sensitivity Analysis of Kernel Estimates: Implications in Nonlinear Physiological System Identification

Many techniques have been developed for the estimation of the Volterra/Wiener kernels of nonlinear systems, and have found extensive application in the study of various physiological systems. To date, however, we are not aware of methods for estimating the reliability of these kernels from single data records. In this study, we develop a formal analysis of variance for least-squares based nonlinear system identification algorithms. Expressions are developed for the variance of the estimated kernel coefficients and are used to place confidence bounds around both kernel estimates and output predictions. Specific bounds are developed for two such identification algorithms: Korenberg's fast orthogonal algorithm and the Laguerre expansion technique. Simulations, employing a model representative of the peripheral auditory system, are used to validate the theoretical derivations, and to explore their sensitivity to assumptions regarding the system and data. The simulations show excellent agreement between the variances of kernel coefficients and output predictions as estimated from the results of a single trial compared to the same quantities computed from an ensemble of 1000 Monte Carlo runs. These techniques were validated with white and nonwhite Gaussian inputs and with white Gaussian and nonwhite non-Gaussian measurement noise on the output, provided that the output noise source was independent of the test input.     

The pattern of cerebral activity underlying verbal fluency shown by split-dose single photon emission tomography (SPET or SPECT) in normal volunteers

Uptake of 99mTc-Exametazime, a marker of relative regional cerebral blood flow has been determined with Single Photon Emission Tomography (SPET or SPECT) in 20 healthy, elderly female subjects during neuropsychological challenge. Each subject was studied under basal conditions after injection of 125 MBq 99mTc-Exametazime. Without moving the head of the subject, they were scanned again after injection of 375 MBq 99mTc-Exametazime. The second injection was made in 10 subjects during a test of verbal fluency, usually regarded as a test of the integrity of function of the left frontal cortex. In the other 10 subjects the second injection was made during simple verbalization (counting). This method of splitting the normal full dose of 99mTc-Exametazime allows a novel comparison between basal and active conditions for different brain regions. Verbal fluency was associated with reduced uptake bilaterally in the region of the basal ganglia and in left temporal (peri-sylvian) cortex when compared with calcarine cortex, an unstimulated reference sensory area. By contrast, counting produced relative activation, greatest in frontal and parietal areas. Thus, a clinically relevant neuropsychological test can be characterized metabolically by a pattern of regional brain activity, whose localization cannot readily be predicted from classical studies of brain lesions. Reduction of regional uptake may suggest an important role for deactivation or inhibition of function in human cognition. The involvement of basal ganglia and temporal areas is of particular interest in relation to the investigation of functional psychiatric illness.     

A method for the calculation of renal clearance based on a single plasma sample

A formula has been derived for the calculation of renal clearance with the use of a single plasma sample. The formula is based on a one-compartment model. A small correction for non-immediate mixing and non-uniform distribution of the tracer was calculated from empirical data. The accuracy in the calculation method depends on how exactly the distribution volume is known and at what time the blood sample is taken. The expected standard deviation in the clearance value was calculated from data of mean value and spread for the distribution volume of 99Tcm-DTPA. In an investigation of 39 subjects with 99Tcm-DTPA, a standard deviation of 5 to 6 ml/min was obtained in comparison with a standard method for clearance calculation. This value is in good agreement with the expected one.     

An efficient method for estimating the probability of misclassification applied to a problem in medical diagnosis

The problem of estimating the performance of a given classifier on a given data set is discussed for the case when no knowledge is available concerning the underlying distributions. A new method of estimating the probability of misclassification is proposed which yields essentially unbiased results similar to Lachenbruch's U-method with far less computation involved. While no theoretical work is presented, a practical rule of thumb is given for choosing the parameters of the estimator. The results are based on experiments performed with a data set concerning six diseases related to epigastric pain, and underline the importance of reporting performance on both the testing data and the training data. Whereas previous papers have continually reported results with a probability of correct classification as high as 74.3 per cent on the raw data and 92.0 per cent on “processed” data, in this paper it is shown that a much more significant estimate of the probability of correct classification based on this data set is 51.0 per cent.     

Estimation of Trial-to-Trial Variation in Evoked Potential Signals by Smoothing Across Trials

Averaging single trial evoked potential data to produce an estimate of the underlying signal obscures trial-to-trial variation in the response. We describe a method for estimating slow changes in the evoked potential signal by smoothing the data over trials. We discuss the crucial issue of deciding how much to smooth and suggest that an appropriate smoothing parameter is one that minimizes the estimated mean average square error of the smoothed data. Equations to estimate the mean average square error for a one-dimensional local linear regression smoother are presented. Performance of the method is assessed using simulated evoked potential data with several different models of a changing signal and different values of the signal-to-noise ratio. We find that the method rarely imputes trial-to-trial variation to data sets that have an unchanging signal, while it almost always produces less error than averaging when estimating a varying signal. The ability of the method to reveal signal heterogeneity is hampered by very low signal-to-noise ratios. When applied to real auditory evoked potential data from a sample of elderly subjects, the method indicated a changing signal in 35% of all subjects and in 56% of subjects with signal-to-noise ratios above 0.6. Consistent patterns of variation in the auditory evoked potential were present in this sample.