Intersample Interval Research Articles

A Two-Fold Rise of BCR-ABL Transcript Levels Advises BCR-ABL Mutation Analysis in Imatinib-Treated Chronic Myeloid Leukemia (CML) - an Analysis of the Randomized CML-Study IV

▪Introduction: The clonal selection of a mutant BCR-ABL positive clone can be observed in about one of two patients with imatinib-resistant chronic myeloid leukemia (CML). The early detection of BCR-ABL kinase domain mutations is crucial, since it allows to change the tyrosine kinase inhibitor (TKI) regimen in a timely manner and may therefore prevent disease progression and the accumulation of further genetic lesions. European LeukemiaNet (ELN) recommendations suggest a mutation analysis if optimal response criteria are not achieved at 3, 6, 12 or 18 months, or whenever a loss of optimal response occurs (Soverini et al., Blood 2011). Several attempts have been made to derive this indication from a specific increase of BCR-ABL levels. Here we report on the correlation of a rise in BCR-ABL transcript levels and the prevalence of BCR-ABL kinase domain mutations in imatinib-treated patients of the CML-Study IV.Methods: A total of 1,173 patients were enrolled until 2009 and randomized to one of four imatinib-based treatment arms. BCR-ABLIS of 988 patients was determined in 7,876 samples by quantitative RT-PCR in the central laboratory (median sample number per patient: 8.4, range 1-37; median follow up: 34 months, range 0-86), representing the eligible patients for the study. Thereby, the estimated intra-laboratory variance is assumed to be about 20%. A first rise of BCR-ABLIS to at least two-fold and >0.1% between two samples of a patient’s molecular course defined a sample suspected of bearing a mutant BCR-ABL positive clone. A mutation analysis was performed on this critical sample by direct sequencing of ABL exons 4 to 10.Results: A critical rise in BCR-ABLIS was observed in 231 of 988 patients (23%) after a median of 15.2 months on treatment (range 2.8-59.4). In the corresponding sample 33 mutant clones could be detected in 31 patients (13%). Thereby a steeper rise of BCR-ABLIS was correlated with a higher incidence of BCR-ABL mutations in the respective group (table). A total of 18 different mutations could be detected, the most frequent were: M244V, n=7 (21%); E255K, n=4 (12%); T315I, n=3 (9%); L248V, G250E, L387M and F486S, n=2 (6%), respectively. Mutations occur in a substantial proportion (8%) of patients with an only 2 to 3-fold rise of BCR-ABLIS transcript levels (table). Therefore, the most sensitive cut-off should be applied and mutation analysis may be triggered by a doubling of BCR-ABL transcripts at levels >0.1% IS.Conclusion: BCR-ABL kinase domain mutations occur already in a substantial proportion of patients with a doubling of BCR-ABL transcript levels, which should determine mutation analysis.Table 1Rise of BCR-ABL expressionPatients (n)Patients with BCR-ABL mutations (n)Patients with BCR-ABL mutations (%)Inter-sample interval(median, days)2 to 3-fold7268.3983 to 5-fold5036.01005 to 10-fold39410.39910 to 100-fold491020.498> 100-fold21838.1125> 2-fold (total)2313113.4101 DisclosuresHanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Pfizer: Consultancy, Research Funding; ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Surveillance, monitoring and surveys of wildlife diseases: a public health and conservation approach

During the past decades the interest in surveillance and monitoring of wildlife diseases has grown internationally. The main reasons could be the following: a) increased size of many wild populations that host pathogens affecting humans; b) the increased economic relevance of some wildlife disease; c) the role played by infections/diseases in the conservation of some wild endangered species. According to the above-described epidemiological situations there is an international need to develop appropriate strategies for the early detection, monitoring and surveys of infectious diseases in wildlife. The paper reviews the epidemiological assumptions on which disease surveillance, monitoring and survey are, or should be, based. The main conclusions are: 1) wildlife disease surveillance and monitoring are long lasting activities that should be implemented when legal bases are available; 2) a wildlife disease introduced in a free area is more likely to be early detected using passive rather than active surveillance; 3) the definition of the suspect largely affects the sensitivity of the whole passive surveillance; thus the suspected case definition should be modulated according to the level of risk; 4) in both active surveillance and monitoring, sampling plays an important role. The sensitivity of any active surveillance/monitoring system is highly dependent from the sampling unit that we define as: the host subpopulation, whose size can maintain the pathogen during a defined inter-sampling interval . Such definition merges the ecological, epidemiological and mathematical approaches aimed in controlling or eradicating infections in both domestic and wildlife; 5) When dealing with the conservation-disease interface, a standardized risk assessment procedure including risk mitigation has to become the rule. Download the complete issue.

Lattice theory models for space-time sampling of acoustic signals

The space-time sampling of underwater acoustic signals by both fixed and towed arrays of sensors can be modeled by lattice theory. The sampling schedule of a fixed array produces a rectangular space-time lattice while the sampling schedule of an array towed at a uniform velocity produces a trapezoidal lattice. Changing the velocity of a towed array corresponds to changing the skewness of a trapezoidal lattice. Willis and Bresler [IEEE Info. Theory (1997)] established an upper bound on the space-time-bandwidth product of a signal that can be sampled time sequentially by a lattice without aliasing. This upper bound provides a valuable perspective on the tradeoff among the temporal intersample interval, the interelement spacing of sensors, the velocity of the towed array, and the spectral support of signal that can be sampled without aliasing. A towed array with the same interelement spacing and temporal intersample interval can sample signals with broader spectral support than a fixed array. Alternately, a towed array can sample a signal with the same spectral support at a slower rate than an equivalent fixed array decreasing load on the data processing system. [Work supported by ONR.]

Dead-band self-triggered PI control for processes with dead-time

Current implementations of digital controllers assume that sensing, control and actuation are performed in a periodic fashion. In classic control schemes, where sensors and controllers are directly connected, periodicity does not provide particular drawbacks, but, in the case of wireless sensor networks, such a choice may be questionable. One of the driving constraints in the design of wireless sensor networks is represented by its energy efficiency, and it has been shown that the main cause of energy consumption is due to the radio activities of the sensor nodes. By using periodic implementations, the sensor nodes are enforced to keep on transmitting measurements to the controller even if it is not really needed, thus wasting energy. To cope with these problems, self-triggered control was recently introduced. This technique aims at reducing the conservativeness of periodic implementations providing an adaption of the inter-sampling intervals based on the current output of the system. Existing work on self-triggered control considers linear systems controlled by state feedback controllers under the assumption of small time-delays. In this paper the problem of designing a self-triggered control scheme that applies to first-order processes with large dead-times controlled by PI controllers is addressed. Moreover, the proposed self-triggered scheme is robust with respect to set-point changes and external disturbances, which are typical in process industry. The results are validated by simulations.

Beryllium-7 activity concentration in plants on the Loess Plateau, China

The activity concentration of beryllium-7 (7Be), a naturally occurring cosmogenic radionuclide produced in the upper atmosphere, was measured in plants on the Loess plateau of China during the growing season of 2005. The 7Be mass activity concentration on July 27 ranged from 34.8 to 147.1 Bq kg−1 in herbaceous plants, from 47.6 to 116.1 Bq kg−1 in subshrubs, and from 15.7 to 56.8 Bq kg−1 in crop plants. The 7Be mass and areal activity concentrations of a mixture of herbaceous plants increased from 66.8 to 288.7 Bq kg−1 and from 0.7 to 46.5 Bq m−2, respectively, during the growing season. On an areal basis, the fraction of 7Be in plants in the soil–plant system increased from 0.4 to 8.4% during the growing season. Positive linear correlations were found between the increases of 7Be mass and areal activity concentrations in the inter-sampling intervals and the amount of precipitation.

A more accurate representation of the expected number of false alarms in statistical quality control

We explain deviations away from the usual estimate of the expected number of false alarms per unit time in the use of a Statistical Process Control (SPC) chart. Using applied probability we develop an exact analytic expression for the expected number of false alarms per unit time. The derivation involves determining the expected value of a modulus function of a random variable. Results depend upon the probability distribution of a key random variable: the time from when an out-of-control signal is observed (and an assignable cause is present) until the process is put back into control. For the cases of normal and Erlang distributions, the usual estimate used in the design of economic control charts is biased somewhat low. The bias becomes more important when there is an appreciable chance of the process going out of control within a single inter-sampling interval.

Temporal coupling of luteinizing hormone and follicle stimulating hormone secretion in polycystic ovary syndrome

The aim of this study was to assess the luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile secretion and their temporal relation (concordance) in subjects with polycystic ovary syndrome(PCOS). Fifteen subjects were included in the study (age 17–30 years ,body mass index (BMI) 19.38–33.46 kg/m2). For the LH and FSH determinations ,blood sampling started at 23.00and lasted for 6 h with an intersample interval of 10 min. Pulse analysis was carried out using the PulsDetekt program. LH/FSH pulse concordance was calculated using the specific concordance index. Gonadotropinco-pulsatility was found in six subjects who were significantly younger than the others (median 18.5 vs. 22.5 years ,p = 0.036). BMI ,hirsutism grade ,insulin sensitivity ,estradiol ,progesterone,testosterone ,prolactin ,cortisol and results obtained from the pulsatility analysis did not significantly differ between the groups. A serum cortisol concentration was correlated with the increased LH/FSHlag time (ρ = 0.851 ,p = 0.036) all subjects were included. In conclusion ,two distinct LH/FSH secretory patterns were found in PCOS patients ,manifested by the presence or absence of the concordanceof gonadotropin secretion. In the group where LH/FSH co-pulsatility was present ,correlation was found between the serum cortisol and the LH/FSH lag. We also confirmed the finding of previous studies thatLH and FSH secretion are regulated by two different mechanisms.

SIMPLE ASYMPTOTIC STABILIZING CONTROL LAWS FOR LINEAR TIME-INVARIANT HYBRID SYSTEMS

This paper deals with the derivation of simple asymptotically stabilizing control laws for linear time-invariant hybrid systems, namely those that consist, in general, of coupled continuous-time and digital and or discretetime ones. The design philosophy consists of two steps. First, the synthesis of an asymptoticallystabilizing control law for the hybrid system at sampling instants is performed through the derivation of an auxiliary extended discrete system. Such a system contains both the digital substate and the discretization at sampling instants of the continuous-time substate. Subsequently, an incremental control law, which acts in between sampling instants, is synthesized to ensure the maintenance of global asymptotic stability during the intersample interval. The synthesis of the incremental control is based on small-gain type arguments related to the incremental controller. The related stability analysis is performed with the natural extension of the description on the intersample intervals of the state trajectory of the auxiliary extended system. Special emphasis is given to the use of multirate sampling as a tool for the synthesis of globally asymptotically stabilizing controls. Multirate control is an important tool to accommodate sampling of different signals in the loop at their natural sampling rates and also for noise-filtering purposes see, for instance Berg et al., 1986a; De la Sen, 1986a, 1996a, 1996b . In particular, faster input input and output sampling is shown to relax the conditions for asymptotic stabilization at sampling instants through state output feedback.

An economic study of [formula omitted] with warning limits

Professors W. K. Chiu and K. C. Cheung (1977) concerned with the economic design of X- charts with warning limits. This paper presents a simpler search procedure, which is implementable in real time on a personal computer, to get optimal determinations of the parameters n (the sample size), k α (the action limit), k w (the warning limit) and h (the intersample interval) of X- charts with warning limits. The results and the execution times of all numerical examples show that our search procedure is quite efficient and accurate indeed.

Constant beamwidth IIR lowpass filter for data sampled at nonuniform rate

A simple modification to the algorithm for a first-order infinite impulse response lowpass filter to allow the use of nonuniformly sampled data is described. This real-time algorithm uses measurements of the intersample interval to modify the recursion weight so that the filter cutoff frequency is kept constant.

Multivariate control charts: an optimization approach to the effective use and measurement of performance

This article presents an economic model that can be optimized to obtain the sample size, the intersample interval, and the upper control limit that minimize the cost of operating a multivariate control chart (MCC). Goel's algorithm has been extensively modified and applied to obtain numerical solutions. A study of the effects of correlation on the efficiences of the MCC shows that, for two variable characteristics, its economic and efficiency increase as the value of correlation coefficients varies from 1 to -1. Furthermore, the article demonstrates that the MCC is economically more efficient than the X̄-chart.

Consequences of non steady-state CO 2 production for accuracy of the doubly labelled water technique: The importance of recapture interval

1. 1. Most applications of the doubly labelled water technique involve measurements of daily energy expenditure. Inter-sample intervals, however, rarely span exactly 24 hr. 2. 2. When estimates made over periods which do not exactly equal 24 hr are corrected to a daily, or hourly rate, and when CO 2 production is also variable, an error is introduced. 3. 3. By computer manipulation of data on the bioenergetics of pregnancy and lactation in bats, and by reanalysis of these data taking inter-sample interval into account, it is shown that the error resulting from intervals deviating from 24 hr, increases with the temporal variability in CO 2 production, the time of sampling relative to activity periods, and the deviation from 24 hr. 4. 4. The error varies between 2 and 7% for each hour the inter-sample period exceeds or is less than 24 hr. This error generally exceeds any analytical error in the technique. 5. 5. It is suggested that all future doubly labelled water studies should attempt to make inter-sample intervals as close as possible to 24 hr (or a multiple thereof). 6. 6. Where samples deviate by more than 1 hr from 24, any analysis should include the inter-sample interval as an independent variable and correct for this artifactual effect before any biological interpretation of the variability is attempted.

Optimal strategies for monitoring a variable subjected to random changes

A criterion is presented for selecting the number of samples and intersample interval time in the monitoring of a variable subjected to random fluctuations. The criterion consists in minimizing both the covariance error of the estimate of the variable and the cost of the monitoring program. By solving this two-objective minimization problem, the Pareto set of optimal solutions is obtained. Finally, an example based on actual data is given.

Use of Curtailed Sampling Plans in the Economic Design ofnp-Control Charts

An expected-cost model is developed for the np-control chart when curtailed sampling procedures are followed. The total expected cost consists of the cost of sampling, the cost of investigating and possibly correcting the process when an out-of-control signal is received, and the cost of producing defectives. A Hook–Jeeves search procedure is used to identify the minimum-cost sampling policy as a function of three design variables: rejection number, maximum sample size, and intersample interval. Numerical examples are presented, and comparisons are made to corresponding complete sampling policies. These results indicate that curtailed sampling plans provide cost improvements over traditional complete sampling plans and are, therefore, to be recommended whenever it is appropriate to use them.

Evaluation of a rapid breath hydrogen analyzer for clinical studies of carbohydrate absorption.

A second-generation gas chromatograph for the analysis of H2 in expired air has been developed. It incorporates a solid-state detector with high sensitivity for H2 and has a small, internal pump which supplies air as the carrier gas, thus eliminating the need for a large tank of compressed gas for the carrier. A reference gas of known H2 concentration is, of course, still required. The entire system weighs 6.0 kg and is completely portable, requiring only 120 V electric current for use. The instrument has a mean intersample interval of less than 2 min, with H2 concentration registered on a digital display. The output has a track-hold feature which permits the output, in parts per million H2, to be retained by the meter so the reading can be verified. The chromatogram can also be recorded on a conventional analog strip-chart recorder. The sensitivity and precision are superior to those of a thermal conductivity H2 gas chromatograph. Moreover, the rapid response time encourages frequent calibration checks with the reference gas. This analyzer offers significant advantages over previous H2-measuring systems for breath-analysis tests used both for diagnostic clinical practice and for field studies of nutritional assessment.

Proactive interference in monkeys: Delay and intersample interval effects are noncomparable

Two prominent theories of proactive interference in animal memory predict that the effects of varying the interval between the interfering and to-be-remembered stimulus in a delayed-matching-to-sample paradigm ought to be comparable to the effects of manipulating the retention interval. To assess this prediction, monkeys were tested in a situation in which a sample was presented, followed by a variable intersample interval, whereupon a second sample was presented. After a delay interval, a choice test was given between the two stimuli that had served as samples. The correct choice was always the most recently presented sample stimulus, and the initial sample of a sequence provided a potential source of proactive interference. In two experiments, delay interval altered performance, whereas interstimulus interval had little or no effect. In a third experiment, using a small set of sample stimuli, intertriai interval altered proactive interference, but again interstimulus interval had no effect. One way of accounting for these data is in terms of distinct short- and long-term memory processes.

Integrating-input technique for c.c.d.

A simple rearrangement of the usual waveforms and voltage levels on the input terminals of a charge-coupled device can be used to integrate the input signal during the intersample interval. The method automatically provides a lowpass filter characteristic matched to the sampling time and tends to suppress high-frequency components and hence reduces aliasing problems. Adequate linearity and dynamic range are demonstrated.

Variance of the estimate of amplitude distributions

The paper considers the variance of experimental estimates of the amplitude probability density function due to finite record length. Analysis, assuming a normally distributed signal, is presented for both a sampled record appropriate for digital experimental procedures and for the case of a continuous record of relevance to analogue analysis. Particular attention is given to the influence of the autocorrelation function of the examined signal on the variance of the estimate. The results may be useful in the design of experiments to estimate the amplitude probability density function, particularly with regard to the selection of the intersample interval in the case of sampled records. Some experimental results are compared with theoretical predictions.

Economically Optimal Determination of the Parameters of X̄-Control Chart

This paper seeks a theoretical basis for determining the optimal parameters of the X̄-chart under the specified conditions. These parameters are the sample size, the factor determining the spread of the control limits, and the intersample interval. The paper shows how to determine these parameters under sound practical assumptions so that the relevant cost function is minimized. Illustrative examples show how the formulated model can be applied.