bluuebunny/crossref_metadata_2025 huggingface dataset:
Revision of the dual substituent parameter treatment using the DFT‐calculated reaction energies
Authors: Exner Otto , Böhm Stanislav
Published: April 2007

The dual substituent parameter (DSP) data treatment is a broadly used procedure correlating the reaction energies or other physical quantities with two sets of substituent constants, inductive (σI) and resonance (σR). It was here revised using the most extensive sets of experimental reactivities available in the literature and two sets of reaction energies calculated at the level B3LYP/6‐311+G(d,p): acidities of 4‐substituted benzoic acids and 5‐(E)‐substituted penta‐2,4‐diene‐(E)‐acids with 19 or 15 common substituents. The latter two series enabled us to investigate the substituent effects more systematically than it was ever possible with the experimental data; this means in particular separate treatment of the undissociated acid molecules and of their anions, further separation of donor and acceptor substituents. In addition, the standard statistical treatment was improved when testing the significance of the resonance term.

The DSP treatment is not valid generally, this applies both to the standard reference series and to the series commonly investigated. At best, DSP may be considered to hold for donor substituents but the effects of acceptors are much less variable and do not depend on the constants σR nor on any other measure of resonance. The small efficiency of acceptor substituents is due by the fact that the constant functional group (COOH in the standard series) is itself an acceptor. A correct treatment would be to investigate the donor and acceptor substituents separately, donors with an acceptor functional groups, and vice versa; substituents with weak resonance effect should be not included. The popularity and apparent success of the DSP treatment can be attributed to several grounds, most important has been the unbalanced choice of substituents. Copyright © 2007 John Wiley & Sons, Ltd.
Computational studies of the cyclization of thiosemicarbazides
Authors: Siwek Agata , Paneth Piotr
Published: April 2007

While typically cyclodehydration of thiosemicarbazides in acidic media leads to 1,3,4‐thiadiazoles, we have recently shown that under reflux conditions in anhydrous acetic acid the cyclization yields an imidazolidine derivative. The mechanism of this reaction has been characterized theoretically. Calculations indicate that this direction, facilitated by the presence of the CH2CO2 moiety in the N4 substituent is favored over the direction leading toward the thiadiazole product. Formation of the CN bond that closes the five‐member ring appears to be concerted with the departure of ethanol molecule, although the proton transfer from the nitrogen atom to oxygen atom is much more advanced in the transition state. Copyright © 2007 John Wiley & Sons, Ltd.
Investigation of cation complexation behavior of azacrown ether substituted benzochromene
Authors: Fedorova O. A. , Maurel F. , Chebun'kova A. V. , Strokach Yu. P. , Valova T. M. , Kuzmina L. G. , Howard J. A. K. , Wenzel M. , Gloe K. , Lokshin V. , Samat A.
Published: April 2007

The study of the complex formation of 3,3‐diphenyl‐3H‐benzo[f]chromenes containing aza‐18‐crown‐6‐ether, diaza‐18‐crown‐6‐ether or morpholine units with alkali, alkaline earth, heavy and transition metal cations in acetonitrile is reported. The spectroscopic and kinetic behavior of the photomerocyanine isomers of these chromenes is strongly affected by complexation with a metal cation. In order to interpret some of experimental data, an ab initio theoretical analysis of photochromic‐crown ether and its cation complexes was conducted. The different site of coordination of mono‐ and divalent cations to determine the minimum‐energy structure of benzochromene complexes in gas phase as well as in acetonitrile as solvent was explored. The coordination of both carbonyl oxygen and crown‐ether macrocyle with divalent cations in carbonyl‐capped structure is found to be the most stable isomer in gas as well as in condensed media. The crown‐containing benzochromenes were studied in liquid‐liquid extraction experiments toward there capacity to transfer metallic salts from water into an organic phase.The high selectivity to extraction of Ag+ was found. Copyright © 2007 John Wiley & Sons, Ltd.
Rational design of a new class of diffusion‐inhibited HABI with fast back‐reaction
Authors: Iwahori Fumiyasu , Hatano Sayaka , Abe Jiro
Published: April 2007

The fast reversible photochromic molecule was synthesized with the aid of triphenylimidazolyl radicals (TPI˙) and naphthalene linker. The crystal structure, photochemical properties, and kinetics of the target compound (1,8‐TPID‐naphthalene) were investigated. 1,8‐TPID‐naphthalene photochemically cleaved into 1,8‐bisTPI˙‐ naphthalene and the color of the solution changed from colorless to green. ESR spectroscopy detected the light‐induced triplet radical pair in frozen matrix. After the UV irradiation is ceased, the back‐reaction of 1,8‐bisTPI˙‐naphthalene occurred by thermal conversion in the dark. The kinetic study on the back‐reaction revealed that the reaction obeys the first‐order kinetics with 2.04 s of half‐life time at 295 K. The activation energy and frequency factor of the back‐reaction were determined as 42.0 kJ/mol and 9.25 × 106 s−1, respectively. Copyright © 2007 John Wiley & Sons, Ltd.
Cumulative π‐π interaction triggers unusually high stabilization of linear hydrocarbons inside the single‐walled carbon nanotube
Authors: Dinadayalane T. C. , Gorb Leonid , Simeon Tomekia , Dodziuk Helena
Published: May 2007

The interactions of linear hydrocarbons C2nH4 and C2nH2 (n = 1–4) with a finite‐length armchair (5,5) single‐walled carbon nanotube have been investigated using HF and MP2 methods in conjunction with 6‐31G(d) basis set, and molecular mechanics (MM) with MM2 force field. In all cases, the results obtained at MP2/6‐31G(d) level show stabilization of these supramolecular systems, contrary to the repulsive interactions obtained with the HF method. The interaction energies computed using MM with MM2 force field are in close agreement with the results obtained using the MP2/6‐31G(d) level. They increase gradually as the length of linear hydrocarbon chain increases. The present study indicates that cumulative π‐π interaction is the origin for the exceptionally high stabilization of the long nanotube‐hydrocarbon complexes. Mulliken population analysis reveals a very small charge transfer between the nanotube and the guest. Essentially there is no change in HOMO‐LUMO energy gap by the insertion of linear hydrocarbons. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Dipole induced photodetachment dynamics of halide anions
Authors: Mondal Chandan Kumar
Published: May 2007

In this article the dynamics of photodetachment from closed shell anion in the presence of two color (bichromatic) laser field have been explored in the context of polar environmental situation. The electronic states of halide ions are modeled by a one dimensional Hamiltonian with a potential V(x) = −V0e. The two parameters V0 and σ are fixed by requiring V(x) to reproduce the experimentally observed ground state ionization energy of the halide ion concerned. The potential so generated are shown to support only one bound state. The time‐dependent Fourier grid Hamiltonian method is used to follow the detachment dynamics with fairly high intensities of light. The environmental effects on the dynamics are sought to be modeled by two ways i) allowing the well depth (V0) to fluctuate randomly V0(t) = V0[1+ΔVR(t)]; R(t) randomly fluctuates between +1 and −1 with time, when ΔV (strength of fluctuation) is fixed and ii) in the presence of perturbation produced by a neighboring solvent dipole, which changes the effective potential. The detachment rate constant is studied as a function of important system parameters of the used light field. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008
Nonempirical calculations of nonlinear optical properties of p‐nitroaniline in acetone: Comparison of supermolecule and semicontinuum approaches
Authors: Balakina Marina Yu. , Fominykh Olga D.
Published: May 2007

The comparison of the conventional continuum, supermolecule, and semicontinuum models for the description of solvent effect on the (hyper)polarizability of p‐nitroaniline (PNA) in acetone is performed. The supermolecule approach is used for the clusters containing PNA and one or two acetone molecules. The account of the specific solute–solvent interactions via the hydrogen bonds formation is shown to result in the enhancement of (hyper)polarizability values. The continuum approach exploited in the framework of polarizable continuum model (PCM) was shown to describe mainly the solvent effect on (hyper)polarizability. The semicontinuum approach, accounting explicitly the interaction between PNA and solvent molecules and treating the rest of the solvent as a continuum, results in a moderate increase of the (hyper)polarizability values compared to those obtained within the conventional PCM approach. All the calculations of (hyper)polarizabilities are performed at the Hartree–Fock level in the aug‐cc‐pVDZ' Dunning basis set. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Structure and relative energies of regioisomers and valence isomers of C60 adducts. HF and DFT study
Authors: Zverev Vladislav V. , Kovalenko Valeriy I. , Romanova Irina P. , Sinyashin Oleg G.
Published: May 2007

Fullerene C60 and N‐bridged C60NH regioisomeres are investigated by HF and DFT methods with BLYP, B3LYP and PBE functionals at the 6‐31G**, 6‐311G** and TZ2P levels. Method DFT/PBE/TZ2P, providing the good compliance with experimental results, is chosen. Cross‐sections of potential energy surface of adducts at a variation of 5,6‐ or 6,6‐ bonds lengths are investigated. It is shown, that C60C2H4NH and C60H2 are characterized by local minima for [5,6]‐closed forms, whereas local minima for [5,6]‐open forms are absent. So absence of stable conformations of the [5,6]‐closed forms of methanofullerenes and aziridinofullerenes is a consequence of strain energy in three‐membered rings. It is shown that relative stability of the regioisomers depends from the lengths of single or double bonds of monoadducts, participating in reactions. The coordinated change of relative energies of the open and closed isomers N‐bridged mono‐(C60NR 1–7) and bis‐adducts (C60(NR)2 8–14) is revealed. The [6,6]‐closed form is more stable for compounds C60NR (2,3) and cis‐1‐C60 (NR)2 (9,10) (R = Me, Ph), while [5,6]‐open and cis‐1 [6,6]‐open forms are more stable for compounds C60NR (6,7) and cis‐1‐C60(NR)2 (13,14) (R = COOMe, R*‐the nitropyrimidine), what has been confirmed by experiment. The factors, defining relative isomers stability are investigated. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Adjusting Moran'sIfor population density
Authors: Oden Neal
Published: April 2007

I derive two new statistics,IpopandI*pop, that adjust Moran'sIto study clustering of disease cases in areas (for example, counties) with different, known population densities. A simulation of Lyme disease in Georgia suggests that these new statistics can be more powerful than those currently in use. This is because they consider both spatial pattern and non‐binomial variance in rates as evidence supporting disease clusters.
A direct approach for correcting aids incidence: Variance formula and comparison with other methods
Authors: Alioum Ahmadou , Commenges Daniel
Published: April 2007

We present a direct approach for correcting the acquired immunodeficiency syndrome (AIDS) incidence data for reporting delays, based on a non‐parametric method for the analysis of right truncated data. We show that the proposed method when applied for grouped data is equivalent to three other published methods. We give a simple formula for the variance of the estimated AIDS incidence. Both estimator and variance are assessed in a simulation study. It is important for the estimation of AIDS incidence in the last quarter of the period under consideration to use month rather than quarter or half‐year as the time unit for the analyses. The method is illustrated using data from the United States Centers for Disease Control.
Confidence intervals, hypothesis tests, and sample sizes for the prevented fraction in cross‐sectional studies
Authors: Gargiullo Paul M. , Rothenberg Richard B. , Wilson Hoyt G.
Published: April 2007

The prevented fraction (PF) is the proportion of disease occurrence in a population averted due to a protective risk factor or public health intervention. The PF is not equivalent to the population attributable risk (AR). The AR is appropriate for epidemiologic studies of disease etiology, and for estimating the potential impact of modifying risk factor prevalence. The PF more directly measures the impact of public health interventions, however, and thus is an important evaluation tool. We derived the variance of the estimated PF by using maximum likelihood theory for cross‐sectional studies. We used simulations to compare the performance of confidence intervals based on various transformations of the estimated PF. The logit transformation was the best choice when PF ≥ 0·3, whereas the untransformed estimate was best when PF < 0·3. We present formulae for hypothesis testing and sample size calculations, discuss the issues of interaction and confounding and give two estimators adjusted for confounding.
Statistical issues in the regulation of medicines
Authors: Lewis John A.
Published: April 2007

The recent release within the European Union of a draft Note for Guidance from the Commission for Proprietary Medical Products (CPMP) entitled ‘Biostatistical methodology in clinical trials in applications for marketing authorisations for medicinal products’ has stimulated widespread discussion of the relevant statistical issues. This discussion contains echoes of an earlier debate concerning a closely related U.S. Guideline. The areas of agreement and disagreement between the two guidelines bear close examination as they provide lessons for all statisticians involved in the design and analysis of clinical trials. Notable areas of debate include crossover designs, multi‐centre trials, the intention to treat principle, pre‐specification of statistical analysis and the ability to generalize results to the wider population of patients. The consequences for the routine involvement of statisticians in this area of work in general, and in the regulatory process in particular, are espicially important. This is an illustration of the extent to which drug regulation has influenced, and is continuing to influence, the development of medical statistics throughout the world.
Comparison of additive and multiplicative models for reproductive risk factors and post‐menopausal breast cancer
Authors: Lund Eiliv
Published: April 2007

The mathematical multistage model of carcinogenesis proposed by Breslow and Day indicates that if hormonal risk factors for breast cancer are late‐stage carcinogens then the use of an additive model (excess absolute risk) should be preferrable to the present standard use of the multiplicative model (excess relative risk). To test different models, information from a large prospective study of 431,604 women aged 45–74 years in 1970 with follow‐up to 1985 on reproductive factors and post‐menopausal breast cancer mortality was used to compute goodness‐of‐fit statistics. The relative risk function, ranging from multiplicative to additive, was explored by changing the exponent in a power transformation. The analysis found evidence of better fit by the additive compared with the multiplicative models, consistent with the proposed mathematical model.
Modelling covariate effects in observer agreement studies: The case of nominal scale agreement
Authors: Graham Patrick
Published: April 2007

Correction for chance‐expected agreement has become an accepted technique in the analysis of observer agreement data and may be particularly useful when the level of agreement achieved in different populations is compared. However, formal methods for making comparisons of chance‐corrected agreement or, more generally, for studying the effects of covariates on chance‐corrected agreement have not received much attention. For nominal scale agreement data we show how Tanner and Young's model for observer agreement can be applied to this problem. The models discussed can be fitted using existing software and certain model parameters have interpretations in terms of positive and negative agreement odds ratios. The proposed methodology facilitates investigation of issues such as confounding of covariate effects and interaction between covariates in their effect on chance‐corrected agreement. The methods outlined therefore allow observer agreement data to be analyzed in a manner strongly analogous to the logistic modelling of the association between disease and suspected risk factors. The methods are illustrated using data on the comparability of primary and proxy respondent reports of the primary respondents participation in physically vigorous leisure time activity.
Bayesian sequential monitoring designs for single‐arm clinical trials with multiple outcomes
Authors: Thall Peter F. , Simon Richard M. , Estey Elihu H.
Published: April 2007

We present a Bayesian approach for monitoring multiple outcomes in single‐arm clinical trials. Each patient's response may include both adverse events and efficacy outcomes, possibly occurring at different study times. We use a Dirichlet‐multinomial model to accommodate general discrete multivariate responses. We present Bayesian decision criteria and monitoring boundaries for early termination of studies with unacceptably high rates of adverse outcomes or with low rates of desirable outcomes. Each stopping rule is constructed either to maintain equivalence or to achieve a specified level of improvement of a particular event rate for the experimental treatment, compared with that of standard therapy. We avoid explicit specification of costs and a loss function. We evaluate the joint behaviour of the multiple decision rules using frequentist criteria. One chooses a design by considering several parameterizations under relevant fixed values of the multiple outcome probability vector. Applications include trials where response is the cross‐product of multiple simultaneous binary outcomes, and hierarchical structures that reflect successive stages of treatment response, disease progression and survival. We illustrate the approach with a variety of single‐arm cancer trials, including bio‐chemotherapy acute leukaemia trials, bone marrow transplantation trials, and an anti‐infection trial. The number of elementary patient outcomes in each of these trials varies from three to seven, with as many as four monitoring boundaries running simultaneously. We provide general guidelines for eliciting and parameterizing Dirichlet priors and for specifying design parameters.
A Bayesian group sequential design for a multiple arm randomized clinical trial
Authors: Rosner Gary L. , Berry Donald A.
Published: April 2007

Group sequential designs for randomized clinical trials allow analyses of accruing data. Most group sequential designs in the literature concern the comparison of two treatments and maintain an overall prespecified type I error. As the number of treatments increases, however, so does the probability of falsely rejecting the null hypothesis. Bayesian statisticians concern themselves with the observed data and abide by the likelihood principle. As long as previous analyses do not change the likelihood, these analyses do not change Bayesian inference. In this paper, we discuss a group sequential design for a proposed randomized clinical trial comparing four treatment regimens. Bayesian ideas underlie the design and posterior probability calculations determine the criteria for stopping accrual to one or more of the treatments. We use computer simulation to estimate the frequentist properties of the design, information of interest to many of our collaborators. We show that relatively simple posterior probability calculations, along with simulations to calculate power under alternative hypotheses, can produce appealing designs for randomized clinical trials.
Linking public health data using geographic information system techniques: Alaskan community characteristics and infant mortality
Authors: Andes Nancy , Davis Jack E.
Published: April 2007

This article identifies geographical contexts important in differentiating infant mortality in Alaska and uses spatial processing models to link and analyse multi‐source data. Information characterizing geographical locations are collected from Alaska's vital statistics for the years 1982–91 and the 1990 Census. Geographic information system (GIS) techniques are applied to identify spatially homogeneous regions, assess spatial compatibility across databases, and allocate geographical units across boundaries. A primary goal of this paper is to encourage spatial linkage and analysis techniques for vital statistics and census data. By demonstrating the interplay of tabular, graphical, and mapping techniques on Alaskan infant mortality, this analysis describes procedures for conducting epidemiological research with data spatially defined at distinct geographical levels.
Evaluating the quality of anonymous record linkage using deterministic procedures with the New York state aids registry and a hospital discharge file
Authors: Muse Alison G. , Mikl Jaromir , Smith Perry F.
Published: April 2007

Linkage of same‐person records across multiple databases relies on high‐quality, uniformly available identifying information. These data quality issues become increasingly important when personal names are not available for record linkage. Using deterministic decision criteria, we linked records from two population‐based files in the absence of personal names. The sensitivity of anonymous record linkage procedures ranged from 32 to 85 per cent for the two years studied, and the positive predictive value (PPV) ranged from 14 to 99 per cent. Decreasing sensitivity and PPV were primarily attributed to (1) errors in computerized identifying information and (2) the deterministic decision criteria specified for record linkage. An evaluation of the contribution of personal names to the quality of record linkage found no measurable impact.
Verification of information in a large medical database using linkages with external databases
Authors: Shevchenko Ivan P. , Lynch John T. , Mattie Angela S. , Reed‐Fourquet Lori L.
Published: April 2007

Efforts to utilize Uniform Hospital Discharge Data Sets (UHDDS) for epidemiological studies have been hampered by the limitations of those databases. The purpose of this paper is to illustrate that linking to external databases can provide the verification necessary to overcome many of those limitations. This method has dramatically altered study design at the Connecticut Hospital Research and Education Foundation and has provided an efficient method for specifying data collection weaknesses within the resident databases.
Multiple hypothesis tests in multiple investigations
Authors: Caudill Samuel P. , Hill Robert H.
Published: April 2007

Inferential statistical methods have traditionally been based on the assumption that one experiment is performed and that interest centres on one or more predetermined hypothesis tests. Exploratory research, on the other hand, often involves multiple hypotheses or repeated investigations under similar or different conditions or both. Several techniques have been proposed to deal with multiple or simultaneous hypothesis testing in single investigations, and procedures to combine observed significance levels for an individual hypothesis test from two or more investigations have been suggested. In this paper we propose a method for identifying important results from multiple statistical tests in multiple investigations. The method is illustrated by using high performance liquid chromatography to identify potential aetiologic contaminants in L‐tryptophan samples.
Feasibility of contour mapping epidemiological data with missing values
Authors: Nobre Flavio F. , De Macedo Marcia M. A.
Published: April 2007

Data of epidemiologic interest often occur as spatial information during each of several time periods. In most cases data are available from a set of regions or localities which can be viewed as points in a plane. Although contour mapping is useful for displaying these data, the lack of data for all data points in a region may lead to erroneous interpretation. In this paper we use simulation to investigate the impact of missing data points for contour mapping using two distinct simulated spatial—time distributions for epidemiologic variables. A model for the occurrence of malaria in localities randomly distributed in one region is chosen as the prototype for data generation.
The price and purity of cocaine: The relationship to emergency room visits and death, and to drug use among arrestees
Authors: Hyatt Raymond R. , Rhodes William
Published: April 2007

This paper examines the relationship of the price and purity of cocaine to emergency room visits and deaths associated with cocaine use and to cocaine use among arrestees. A model is developed for the trend in cocaine prices at the retail level during the period January 1986 to December 1991. This trend is then compared to information on emergency room visits, medical examiner reports, and the percentage of arrestees testing positive for cocaine use over the same period. The principal conclusion is that there is a significant negative relationship between the estimated street price of cocaine and the level of related medical emergencies and deaths and the number of arrestees who test positive for cocaine.
Statistical issues in assessing comorbidity
Authors: Kraemer Helena Chmura
Published: April 2007

I define three separate and distinct types of non‐random comorbidity: epidemiologic, clinical and familial. These might exist singly or in any combination for a pair of disorders. The focus is on their definition and the measurement and interpretation of the types of comorbidity of most common concern: epidemiologic comorbidity. I discuss certain sources of epidemiologic comorbidity such as shared risk factors, or diagnostic ‘fuzziness’, and I indicate the directions of research design and analyses to disclose such sources.
Logistic regression in case‐control studies: The effect of using independent as dependent variables
Authors: Nagelkerke Nico J. D. , Moses Stephen , Plummer Francis A. , Brunham Robert C. , Fish David
Published: April 2007

In case‐control studies, cases are sampled separately from controls. In such studies the primary analysis concerns the estimation of the effect of covariables on being a case or a control. To explore causal pathways, further secondary analysis could concern the relationships among the covariables. In this paper the validity of such secondary analysis is addressed. In particular, the use of multiple logistic regression in case‐control studies where the dependent variable is not the case/control indicator is explored. It is shown that only under very restrictive conditions will sample regression coefficients correctly estimate their true value. In many situations, it may be valid to regress one covariable on others in the control group, but not in the case group or the combined sample. This principle is illustrated by a study of sexually transmitted disease in Kenya.
Percentile regression analysis of correlated antibody responses
Authors: Moulton Lawrence H. , Holt Elizabeth A. , Job Jayakaran S. , Halsey Neal A.
Published: April 2007

Antibody responses following vaccination usually are analysed by comparing geometric mean concentrations across levels of relevant covariates and by comparing the proportions of vaccinees responding. In the regression setting, the analyses are done on log‐transformed concentrations, estimating geometric mean responses conditional on a vector of covariates. More detailed analyses examining the relationship of covariates to different parts of the response distribution may be performed through the application of asymmetric least squares estimation of regression percentiles. We present a method for accounting for correlation in percentile regression analyses of longitudinal antibody response data. We illustrate the procedures with measles antibody response data from Haitian children who participated in a randomized trial of high titre vaccines. The strongest dose and strain effects were seen in the low end of the antibody concentration distributions.
The log transformation is special
Authors: Keene Oliver N.
Published: April 2007

The logarithmic (log) transformation is a simple yet controversial step in the analysis of positive continuous data measured on an interval scale. Situations where a log transformation is indicated will be reviewed. This paper contends that the log transformation should not be classed with other transformations as it has particular advantages. Problems with using the data themselves to decide whether or not to transform will be discussed. It is recommended that log transformed analyses should frequently be preferred to untransformed analyses and that careful consideration should be given to use of a log transformation at the protocol design stage.
AN EXTENSION OF THE CONTINUAL REASSESSMENT METHODS USING A PRELIMINARY UP‐AND‐DOWN DESIGN IN A DOSE FINDING STUDY IN CANCER PATIENTS, IN ORDER TO INVESTIGATE A GREATER RANGE OF DOSES
Authors: Møller Susanne
Published: April 2007

In a phase I clinical trial in cancer patients, the drug involved had one known main adverse effect, which also occurs spontaneously in cancer patients with a fairly high frequency. Experiments in rats have shown marked effects of the drug on tumour growth in high doses, but also dose‐dependent toxicity. Consequently, the aim of the study was to determine a dose with a prespecified, acceptable rate of toxicity. As a traditional design could result in inaccurate conclusions, use of the continual reassessment method (CRM) was considered. Twelve dose levels were chosen, allocating to the first patient the lowest, but safe, dose. It is likely that the target dose is far above that, and that CRM then would escalate too fast, skipping certain levels. To ensure that all dose levels inferior to the target dose was tried, some combined methods were proposed: (1) an extension of the design, combining the CRM with a preliminary up‐and‐down design in order to reach the neighbourhood of the target dose during a successive escalation, and (2) a restriction on the CRM of never escalate more than a single dose level. Simulations showed the extended CRM to be superior by making it possible to investigate a greater range of doses using fewer patients, and to provide more accurate estimates.
ESTIMATING THE MINIMUM THERAPEUTICALLY EFFECTIVE DOSE OF A COMPOUND VIA REGRESSION MODELLING AND PERCENTILE ESTIMATION
Authors: Filloon Thomas G.
Published: April 2007

Estimation of the minimum effective dose (MED) of a compound from a typical placebo‐controlled dose‐response study can be carried out in several ways. Current approaches compare treatment doses against a placebo dose via selected contrasts to determine the lowest dose level at which the contrast is statistically significant. Ruberg shows how this approach works for various choices of contrasts. Instead, the MTED (minimum therapeutically effective dose) might be defined as the lowest dose level that yields a therapeutic benefit to patients, on average, or to a given percentage of patients. One could use a lower confidence limit for the mean approach to determine the dose yielding (on average) a therapeutic benefit via regression modelling of the continuous treatment dose response. More importantly, a patient relevant approach would be to actually estimate regression percentiles or construct regression tolerance intervals. Such an approach addresses the question ‘What percentage of patients are receiving therapeutic (yet safe) doses’, instead of just knowing that a dose is effective ‘on average’, and thus would help to understand the distribution of patient responses at a given treatment dose. This further enables one to better evaluate the efficacy versus safety trade‐off as dose increases and provides better guidelines for prescribed dose levels.
USE OF THE REPEATED CROSS‐OVER DESIGNS IN ASSESSING BIOEQUIVALENCE
Authors: Liu Jen‐Pei
Published: April 2007

We consider applications of the repeated 2 × 2 cross‐over design to evaluating bioequivalence between the two formulations. The repeated 2 × 2 cross‐over design allows us not only to assess bioequivalence on average bioavailability and to examine the subject‐by‐formulation interaction but also to obtain independent unbiased estimates of intrasubject variability. One consequence of unequal intrasubject variabilities is that the sum of squares of intersubject residuals and the sum of squares of subject‐by‐formulation residuals are not independent. We also discuss the relative merits of this design as compared to the standard 2 × 2 cross‐over design without repeated measurements in terms of precision and sample size with respect to the ratio of the number of subjects to the repeated measurements per subject. We investigate other uses of the 2 × 2 cross‐over in examining the bioequivalence between the two different dosing regimens. Possible applications of other repeated cross‐over designs to bioequivalence for more than two formulations are explored. A numerical example illustrates the proposed procedure.
DEFINING, MONITORING AND COMBINING SAFETY INFORMATION IN CLINICAL TRIALS
Authors: Enas Gregory G. , Goldstein David J.
Published: April 2007

Assessment of clinical trial safety data for industry, regulatory agencies, medical practitioners and patients requires definition and measurement, monitoring, and overall analysis. Prospective ‘safety’ definitions and reliable measurement tools reduce inefficient data collection and improve the validity of resulting analyses. Statistical tools can help investigators monitor safety data from controlled clinical trials and help improve post‐marketing surveillance. Also, when evaluating overall safety, one needs to assess all available information by combining information from many trials and other sources. Planning for this combined assessment, incorporating flexibility to assess unanticipated yet important nuances in individual trials, may be more important than the actual statistical analysis method used. A keen awareness of the future needs of consumers of this infomation is quite important. Some current proposals to combine safety information will be discussed.
COMPARING THE BIVARIATE EFFECTS OF TOXICITY AND EFFICACY OF TREATMENTS
Authors: Tuber‐Bitter Pascale , Bloch Daniel A. , Raynauld Jean‐Pierre
Published: April 2007

Medical studies often involve comparing the toxicity and efficacy of drugs. Separately evaluating toxicity and efficacy, the usual practice, does not correspond to how doctors manage patients and does not use the information provided in their bivariate relationship. This paper presents methods for analysing the bivariate data. One method is based on assessing the benefit for patient values to lie in different regions of the toxicity–efficacy plane. A second method includes patient thresholds for tolerating drugs. We propose dividing the toxicity–efficacy plane into regions where patients are likely to tolerate the drug. Several statistics are defined on these regions for measuring the toxic–therapeutic relationship, and the bootstrap is proposed for estimating their variances. We illustrate with treatment information available on rheumatoid arthritis patients.
Smoothing splines for longitudinal data
Authors: Anderson Stewart J. , Jones Richard H.
Published: April 2007

In a longitudinal data model with fixed and random effects, polynomials are used to model the fixed effects and smoothing polynomial splines are used to model the within‐subject random effect curves. The splines are generated by modelling the data for each subject as observations of an integrated random walk with observational error. The initial conditions for each subject's deviation from the fixed effect curve are assumed to have zero mean and arbitrary covariance matrix which is estimated by maximum likelihood, producing an empirical Bayes estimate. This is in contrast to modelling a single curve using a diffuse prior. An example is presented using unbalanced longitudinal data from a pilot study in breast cancer patients.
A proportional regression model for 20 year survival of colon cancer in Norway
Authors: Zahl Per‐Henrik
Published: April 2007

Twenty year survival of all Norwegians with colon cancer registered in a period of 10 years is estimated by both relative survival rates, and with a proportional regression model for the excess intensity. Male colon cancer patients have a significant positive excess mortality at least 20 years after diagnosis, while the excess mortality for females is about zero after 10 years. Stratified analyses for men indicate non‐proportionality throughout the follow‐up period, and when this information is included in the regression model, there are significant effects of age between 60 and 70 years and for pelvic cancer. The use of proportional regression models is also discussed when excess intensities are close to zero or negative.
Experimental quantiles of epidemiological indices in case‐control studies with non‐differential misclassification
Authors: Marinos Aristides Th. , Tzonou Anastasia J. , Karantzas Menelaos E.
Published: April 2007

The formulae for some typical epidemiological indices in case‐control studies with non‐differential misclassification are expressed in terms of two groups (α, β) and (γ, δ) of misclassification probabilities of exposure E and confounder C, respectively, and the initially estimated frequencies. The parameters α and β denote the probability that subjects exposed to E are classified as non‐exposed and the probability that non‐exposed ones will be classified as exposed, respectively. Similarly, δ and γ stand for the probability that those who have been exposed to C will be classified as non‐exposed and the probability that non‐exposed subjects are classified as exposed, respectively. The non‐negativeness of the expressions for the ‘true’ frequencies in terms of the measured ones and the misclassification probabilities leads to the construction of feasibility regions for α, β, γ and δ. For a number of ‘acceptable’ 4‐tuples (α, β, γ, δ), all of which lie inside these feasibility regions, a sequence of feasible values for an epidemiological index is determined, after employing a systematic procedure by means of a ‘searching net’ with increments Δα, Δβ, Δγ, Δδ. The procedure serves to determine the characteristics of the (experimental) cumulative distribution function for any selected epidemiological index. The final stage in exploiting the structure of feasibility regions for α, β, γ and δ is to use the cumulative distribution function to calculate quantiles for the index associated with prescribed probabilities.
Risk scores from logistic regression: Unbiased estimates of relative and attributable risk
Authors: Tomasson Helgi
Published: April 2007

In epidemiology, the risk of disease in terms of a set of covariates is often modelled by logistic regression. The resulting linear predictor can be used to define the extent of risk between extremes, and to calculate an attributable risk for the covariates taken together. As is well known, straightforward use of the linear predictor, on the sample from which it was derived, to obtain estimates the relative and attributable risk will be biased, often seriously. Use of the jack‐knife technique is extended to produce asymptotically unbiased estimates of relative and attributable risks. The asymptotic variances associated with these estimates are derived by using the formulae of conditional variances. They are applied to the results of a case‐control study of stomach cancer.
Calculation of unconditional and conditional reference intervals for foetal size and growth from longitudinal measurements
Authors: Royston Patrick
Published: April 2007

Methods for estimating unconditional and conditional reference intervals for foetal size and growth based on longitudinal observations are presented. The methods are based on simple random‐effects regression models and involve transforming both the response and the covariate (timepoint). A dataset from a designed longitudinal study of foetal size is analysed in detail as a motivating example.
Confidence limits for the population prevalence rate based on the negative binomial distribution
Authors: Lui Kung‐Jong
Published: April 2007

This paper shows that the extension of the simple procedure of George and Elston in calculation of confidence limits for the underlying prevalence rate to accommodate any finite number of cases in inverse sampling is straightforward. To appreciate the fact that the length of the confidence interval calculated on the basis of the first single case may be too wide for general utility, I include a quantitative discussion on the effect due to an increase in the number of cases requested in the sample on the expected length of confidence intervals. To facilitate further the application of the results presented in this paper, I present a table that summarizes in a variety of situations the minimum required number of cases for the ratio of the expected length of a confidence interval relative to the underlying prevalence rate to be less than or equal to a given value. I also include a discussion on the relation between Cleman'S confidence limits on the expected number of trials before the failure of a given device and those presented here.
Estimation of a common odds ratio under binary cluster sampling
Authors: Ahn Chul , Odom‐Maryon Tamara
Published: April 2007

We present results from a simulation study for the estimation of a common odds ratio in multiple 2 × 2 tables when the data are correlated within clusters. We model the correlation of the data by the beta‐binomial distribution. Through a simulation study, we compare the Mantel—Haenszel estimator with Rao and Scott'S estimator in terms of their biases, observed variances, relative efficiencies of their variances and 95 per cent coverage proportions. We limit the simulation study to the case where there are the same number of subjects in each cluster and the same number of observations in each row of each stratum. When ρ = 0, we recommend use of the Mantel—Haenszel estimator γMH with an unadjusted variance and Rao and Scott'S estimator γ with a pooled design effect. In general, when ρ >0, we recommend the Mantel—Haenszel estimator γMH with an adjusted variance and Rao and Scott'S estimator γ with a pooled design effect.
Biostatistical concepts and methods in the legal setting
Authors: Gastwirth Joseph L. , Greenhouse Samuel W.
Published: April 2007

Biostatistical concepts and methods apply to various problems arising in actual U.S. legal cases. These involve: measures of association, assessing the potential effect of omitted variables and the Peters—Belson approach to regression. In particular, we present the inapplicability of Fisher's exact test in the case where the process determining the marginal sample sizes is not independent of the hypothesis under study by the 2 × 2 table. We adapt Cornfield's procedure to assess whether the omission of another factor could have contributed to a non‐significant finding of the effect of the major factor under investigation. Finally, we demonstrate the relevance and utility of the Peters—Belson regression methodology to equal pay and promotion cases.
Modelling frailty in area mortality
Authors: Congdon Peter
Published: April 2007

This paper investigates the impact on area life tables of the specification of unobserved frailty. Frailty specification may affect both the regression effects of area and individual level covariates, and lead to changes in the value of summary mortality parameters, such as life expectancy. The paper also investigates how frailty affects life tables for specific causes of death, especially lung cancer and heart disease. Implications for choice between different model specifications, both in terms of age dependence and frailty, are discussed. The focus is on registered deaths recorded by age, birthplace and by small area within a borough of Greater London.
On the use of a pilot sample for sample size determination
Authors: Browne Richard H.
Published: April 2007

To compute the sample size needed to achieve the planned power for a t‐test, one needs an estimate of the population standard deviation δ. If one uses the sample standard deviation from a small pilot study as an estimate of δ, it is quite likely that the actual power for the planned study will be less than the planned power. Monte Carlo simulations indicate that using a 100(1 − γ) per cent upper one‐sided confidence limit on δ will provide a sample size sufficient to achieve the planned power in at least 100(1 − γ) per cent of such trials.
Decision and detection limits for linear homoscedastic assays
Authors: Dunne Adrian
Published: April 2007

This paper focuses on the effect of estimating the calibration parameters on the decision and detection limits for linear homoscedastic assays. Assay decision and detection limits are defined. For linear homoscedastic assays expressions for these limits are derived when the calibration parameters are known and unknwon. These expressions, together with others previously reported in the literature, are used to calculate limits for a particular example of a cyclic AMP assay. The various methods of computing decision and detection limits are compared in a simulation study. The results demonstrate the importance of taking into consideration the variation in the estimators of the calibration parameters.
Sample size determination in stratified trials to establish the equivalence of two treatments
Authors: Nam Jun‐Mo
Published: April 2007

When designing a trial to establish that a new treatment is as effective as a standard one, the conventional test procedure and sample size based on a null hypothesis of no difference between two treatments is inappropriate. Several authors have investigated test statistics and corresponding sample sizes based on the null hypothesis that the standard treatment is more effective than the new by at least some specific value for a single 2 × 2 table. This paper considers a trial that involves several 2 × 2 tables and presents an approximate formula for the sample size required to obtain a given power of a one‐tailed score test for a null hypothesis of a specific common non‐zero difference between two treatments across strata. I show that the sample size for a trial based on an unstratified test is always larger than that based on a stratified test when the design is balanced.
Confidence interval estimates of an index of quality performance based on logistic regression models
Authors: Hosmer David W. , Lemeshow Stanley
Published: April 2007

This paper considers an index of hospital quality performance defined as the ratio of the observed number deaths to the number predicted by a fitted logistic regression model. We study tests and confidence intervals under two different scenarios depending on the availability of an estimate of the covariance matrix of the coefficints from the fitted logistic regression model. We propose parametric as well as bootstrap‐based confidence intervals. We apply the methods to an analysis of the performance of 27 intensive care units.