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Biomedical subjects

A D Tsodikov

Publications and source records attributed to A D Tsodikov.

17 recordsLinked to original sources
PubMed2003

Thermodynamic criteria for high hit rate antisense oligonucleotide design.

Antisense oligonucleotides are used for therapeutic applications and in functional genomic studies. In practice, however, many of the oligonucleotides complementary to an mRNA have little or no antisense activity. Theoretical strategies to improve the 'hit rate' in antisense screens will reduce the cost of discovery and may lead to identification of antisense oligonucleotides with increased potency. Statistical analysis performed on data collected from more than 1000 experiments with phosphorothioate-modified oligonucleotides revealed that the oligo-probes, which form stable duplexes with RNA (DeltaG(o)37 < or = -30 kcal/mol) and have small self-interaction potential, are more frequently efficient than molecules that form less stable oligonucleotide-RNA hybrids or more stable self-structures. To achieve optimal statistical preference, the values for self-interaction should be (DeltaG(o)37) > or = -8 kcal/mol for inter-oligonucleotide pairing and (DeltaG(o)37) > or = -1.1 kcal/mol for intra-molecular pairing. Selection of oligonucleotides with these thermodynamic values in the analyzed experiments would have increased the 'hit rate' by as much as 6-fold.

Chemistry, Pharmaceutical↗
PubMed2003

Thermodynamic calculations and statistical correlations for oligo-probes design.

Optimization of probe design for array-based experiments requires improved predictability of oligonucleotide hybridization behavior. Currently, designing oligonucleotides capable of interacting efficiently and specifically with the relevant target is not a routine procedure. Multiple examples demonstrate that oligonucleotides targeting different regions of the same RNA differ in their hybridization ability. The present work shows how thermodynamic evaluations of oligo-target duplex or oligo self-structure stabilities can facilitate probe design. Statistical analysis of large sets of hybridization data reveals that thermodynamic evaluation of oligonucleotide properties can be used to avoid poor RNA binders. Thermodynamic criteria for the selection of 20 and 21mers, which, with high probability, interact efficiently and specifically with their targets, are suggested. The design of longer oligonucleotides can also be facilitated by the same calculations of DeltaG(o) (T) values for oligo-target duplex or oligo self-structure stabilities and similar selection schemes.

Nucleic Acid Hybridization↗
PubMed2002

Variable selection and pattern recognition with gene expression data generated by the microarray technology.

Lack of adequate statistical methods for the analysis of microarray data remains the most critical deterrent to uncovering the true potential of these promising techniques in basic and translational biological studies. The popular practice of drawing important biological conclusions from just one replicate (slide) should be discouraged. In this paper, we discuss some modern trends in statistical analysis of microarray data with a special focus on statistical classification (pattern recognition) and variable selection. In addressing these issues we consider the utility of some distances between random vectors and their nonparametric estimates obtained from gene expression data. Performance of the proposed distances is tested by computer simulations and analysis of gene expression data on two different types of human leukemia. In experimental settings, the error rate is estimated by cross-validation, while a control sample is generated in computer simulation experiments aimed at testing the proposed gene selection procedures and associated classification rules.

Computer Simulation↗
PubMed2001

A survival model for fractionated radiotherapy with an application to prostate cancer.

This paper explores the applicability of a mechanistic survival model, based on the distribution of clonogens surviving a course of fractionated radiation therapy, to clinical data on patients with prostate cancer. The study was carried out using data on 1,100 patients with clinically localized prostate cancer who were treated with three-dimensional conformal radiation therapy. The patients were stratified by radiation dose (group 1: <67.5 Gy; group 2: 67.5-72.5 Gy; group 3: 72.5-77.5 Gy; group 4: 77.5-87.5 Gy) and prognosis category (favourable, intermediate and unfavourable as defined by pre-treatment PSA and Gleason score). A relapse was recorded when tumour recurrence was diagnosed or when three successive prostate specific antigen (PSA) elevations were observed from a post-treatment nadir PSA level. PSA relapse-free survival was used as the primary end point. The model, which is based on an iterated Yule process, is specified in terms of three parameters: the mean number of tumour clonogens that survive the treatment, the mean of the progression time of post-treatment tumour development and its standard deviation. The model parameters were estimated by the maximum likelihood method. The fact that the proposed model provides an excellent description both of the survivor function and of the hazard rate is prima facie evidence of the validity of the model because closeness of the two survivor functions (empirical and model-based) does not generally imply closeness of the corresponding hazard rates. The estimated cure probabilities for the favourable group are 0.80, 0.74 and 0.87 (for dose groups 1-3, respectively); for the intermediate group: 0.25, 0.51, 0.58 and 0.78 (for dose groups 1-4, respectively) and for the unfavourable group: 0.0, 0.27, 0.33 and 0.64 (for dose groups 1-4, respectively). The distribution of progression time to tumour relapse was found to be independent of prognosis group but dependent on dose. As the dose increases the mean progression time decreases (41, 28.5, 26.2 and 14.7 months for dose groups 1-4, respectively). This analysis confirms that, in terms of cure rate, dose escalation has a significant positive effect only in the intermediate and unfavourable groups. It was found that progression time is inversely proportional to dose, which means that patients recurring in higher dose groups have shorter recurrence times, yet these groups have better survival, particularly long-term. The explanation for this seemingly illogical observation lies in the fact that less aggressive tumours, potentially recurring after a long period of time, are cured by higher doses and do not contribute to the recurrence pattern. As a result, patients in higher dose groups are less likely to recur; however, if they do, they tend to recur earlier. The estimated hazard rates for prostate cancer pass through a clear-cut maximum, thus revealing a time period with especially high values of instantaneous cancer-specific risk; the estimates appear to be nonproportional across dose strata.

Disease-Free Survival↗
PubMed2001

[Parametric survival analysis in patients with cervical cancer following fractionated radiotherapy: a new procedures and results].

A recent theoretical result of Kendal (1998) enabled us to develop a survival model which allows for proliferation of tumor clonogenic cells in the course of fractionated radiotherapy. We explored this model during an analysis of clinical data on survival of 982 patients with cancer of the cervix uteri. The model provided a good description of survival patterns in different groups of patients. The estimated cure probability did not correlate with the rates of cell proliferation between exposures to radiation. Also, our results showed that this parameter cannot be estimated from survival data. Some light has been thrown on the relationship of cell proliferations taking place between exposures, on the one hand, and end-results of treatment for cancer of the cervix uteri, on the other.

Dose Fractionation, Radiation↗
PubMed2000

Identification of sequence motifs in oligonucleotides whose presence is correlated with antisense activity.

Design of antisense oligonucleotides targeting any mRNA can be much more efficient when several activity-enhancing motifs are included and activity-decreasing motifs are avoided. This conclusion was made after statistical analysis of data collected from >1000 experiments with phosphorothioate-modified oligonucleotides. Highly significant positive correlation between the presence of motifs CCAC, TCCC, ACTC, GCCA and CTCT in the oligonucleotide and its antisense efficiency was demonstrated. In addition, negative correlation was revealed for the motifs GGGG, ACTG, AAA and TAA. It was found that the likelihood of activity of an oligonucleotide against a desired mRNA target is sequence motif content dependent.

Base Composition↗
PubMed1999

The shape of the hazard function in breast carcinoma: curability of the disease revisited.

BACKGROUND: The question of curability of breast carcinoma remains controversial. Because the probability of cure essentially is an asymptotic notion, the corresponding estimation problems call for special statistical methods. Such methods should account for an intimate connection between the probability of cure and the shape of the hazard function. METHODS: The study was performed on survival data for 13,166 women with breast carcinoma identified through the Utah Cancer Registry and stratified by clinical stage and age at diagnosis. For these patients, the follow-up period was 30 years. Three estimation procedures were used for estimating the hazard function from the data: the life table estimator, a kernel counterpart of the Nelson-Aalen estimator, and a parametric estimator specifically designed for two-component hazards. The parametric estimate of the hazard function was used to provide estimates of cure rates for each category of patients. RESULTS: For all categories of patients under study, the estimated hazard functions passed through a clear-cut maximum, showing a tendency to decrease as time approached the end of a follow-up period. The hazards appeared to be nonproportional across the strata. The estimated values of the cure rate and the corresponding confidence intervals were determined for each stratum of patients with breast carcinoma. CONCLUSIONS: The results of the current study strongly suggest that cure is a possible outcome of breast carcinoma treatment. The condition of proportionality of risks is not met in breast carcinoma survival data.

Adult↗
PubMed1997

A distribution of tumor size at detection: an application to breast cancer data.

This paper discusses a method of estimating numerical characteristics of unobservable stages of carcinogenesis from data on tumor size at detection. To this end, a stochastic model of spontaneous carcinogenesis has been developed to allow for a simple pattern of tumor growth kinetics. It is assumed that a tumor becomes detectable when its size attains some threshold level, which is treated as a random variable. The model yields a parametric family of joint distributions for tumor size and age at detection. Some estimation problems associated with the proposed model appear to be tractable. This is illustrated with an application to the statistical analysis of data on primary breast cancer.

Adult↗
PubMed1996

A distribution of tumor size at detection and its limiting form.

A distribution of tumor size at detection is derived within the framework of a mechanistic model of carcinogenesis with the object of estimating biologically meaningful parameters of tumor latency. Its limiting form appears to be a generalization of the distribution that arises in the length-biased sampling from stationary point processes. The model renders the associated estimation problems tractable. The usefulness of the proposed approach is illustrated with an application to clinical data on premenopausal breast cancer.

Breast Neoplasms↗
PubMed1995

Discrete strategies of cancer post-treatment surveillance. Estimation and optimization problems.

We consider the cancer post-treatment surveillance to be represented by a discrete observation process with a non-zero false-negative rate. Using a simple stochastic model of cancer recurrence derived within the random minima framework, we obtain parametric estimates of both the time-to-recurrence distribution and the probability of false-negative diagnosis. Then assuming the false-negative rate known, we give a nonparametric maximum likelihood estimator for the tumor latency time distribution. When designing an optimal strategy of post-treatment surveillance, we proceed from the minimum of the expected delay in detecting tumor recurrence as a pertinent criterion of optimality. To solve this problem we give a dynamic programming algorithm. We illustrate the methods by analyzing data on breast cancer recurrence.

Algorithms↗
PubMed1993

A stochastic model of hormesis.

In order to describe the life-prolonging effect of some agents that are harmful at higher doses, ionizing radiations in particular, a stochastic model is developed in terms of accumulation and progression of intracellular lesions caused by the environment and by the agent itself. The processes of lesion repair, operating at the molecular and cellular level, are assumed to be responsible for this hormesis effect within the framework of the proposed model. Properties of lifetime distributions, derived for analysis of animal experiments with prolonged and acute irradiation, are given special attention. The model provides efficient means of interpreting experimental findings, as evidenced by its application to analysis of some published data on the hormetic effects of prolonged irradiation and of procaine on animal longevity.

Animals↗
PubMed1991

On the optimal policies of cancer screening.

Some problems of optimal screening are considered. A screening strategy is allowed to be nonperiodic. Two approaches to screening optimization are used: the minimum delay time approach and the minimum cost approach. Both approaches are applied to the analysis of an optimization problem when the natural history of the disease is known and when it is unknown (a minimax problem). The structure of optimal screening policies is investigated as well as the benefit they can provide compared to the periodic screening policy. The detection probability is assumed to depend only on the stage of the disease, though it may not be constant throughout each stage. It is shown that periodic screening appears to be optimal when one has no information on the natural history of the disease, the minimum delay time criterion being used for optimization. Some applications to lung cancer screening are presented.

Costs and Cost Analysis↗