Unbalanced Treatment Research Articles

Design characteristics that influence attrition in geriatric antidepressant trials: meta‐analysis

To identify study-level and treatment group-level characteristics that are associated with attrition in antidepressant trials for the depressed elderly. This meta-analysis used 68 published antidepressant randomized trials for the elderly depressed. Study-level and treatment group-level variables were extracted. The former consisted of: use of placebo arm, number of arms, unbalanced treatment allocation, year conducted, study duration, study location, number of centers, and patient pool. The latter consisted of: assigned treatments, baseline mean Hamilton Depression Rating Scale (HDRS), baseline mean age, gender ratio, attrition size, and sample size. Univariate logistic regressions with attrition as the dependent variable were applied, followed by application of a forward stepwise selection method for identification of independent attrition correlates. The 68 studies had a total of 153 treatment groups and 8,385 subjects. Among them, 2,287 subjects were terminated early, resulting in an overall 27.3% attrition rate. The stepwise results showed that higher attrition was significantly associated with active antidepressant groups as opposed to placebo groups, higher baseline HDRS, smaller sample size, unbalanced allocation of treatments, longer duration, and studies conducted in USA. The attrition in geriatric antidepressant trials can be affected by study and group-level design characteristics that include severity of depression symptoms and active treatments among others.

The effect of postmenopausal hormone replacement therapy on endometrial bleeding

The aim of this study was to determine the effect of postmenopausal hormone replacement therapy (exclusively oestrogen or sequential/continuous combined oestrogen-progestogen treatment) on endometrial bleeding, including the histological alteration of the endometrium. From January 2000 to December 2005, 5893 women were treated by the authors in the menopause unit of their department. They examined the frequency of menopausal bleeding in treated and control groups. In case of bleeding, dilatation and fractional curettage was always carried out and the tissues were histologically evaluated. In menopausal patients who did not obtain hormone replacement therapy, bleeding occurred twice as frequently as in the treated group. Proliferating or hyperplastic endometrium was observed mainly among the treated patients, suggesting that in due time, even before the age of menopause, hormonal treatment might decrease hyperplasia and indirectly the chance of occurrence of adenocarcinoma. Hyperplasia was found more frequently in patients obtaining only oestrogen. According to the authors' view, unbalanced oestrogen treatment might further aggravate the existing hyperplasia of the endometrium. In the group treated with hormonal therapy, only simplex hyperplasia was observed. No case of complex hyperplasia with atypia was found among these patients. In the majority of patients on continuous balanced hormonal therapy, the myometrium underwent atrophy and the frequency of hyperplasia, including the chance of bleeding, mostly decreased. Endometrial polyps most frequently were found under hormonal therapy, but no acceptable explanation can be provided. The rate of cervical polyps was also higher in this group. According to the observations of the authors, hormone replacement therapy does not increase the risk of endometrial carcinoma. Combined preparations decrease the frequency of hyperplasia and consequently the chance of occurrence of adenocarcinoma.

Self-Consistent Polarization of the Boundary in the Redistributed Charge and Dipole Scheme for Combined Quantum-Mechanical and Molecular-Mechanical Calculations.

The recently developed redistributed charge (RC) and redistributed charge and dipole (RCD) schemes are electrostatic-embedding schemes to treat a quantum-mechanical/molecular- mechanical (QM/MM) boundary that passes through covalent bonds. In the RC and RCD schemes, the QM subsystem is polarized by the MM subsystem, but the MM subsystem is not polarized by the QM one; this results in an unbalanced treatment of the electrostatic interactions. In the work reported here, we developed improved schemes, namely, the polarized-boundary RC scheme (PBRC) and the polarized-boundary RCD (PBRCD) scheme, by adding self-consistent mutual polarization of the boundary region of the MM subsystem to the previous schemes. The mutual polarizations are accounted for in the polarized-boundary calculations by adjusting the boundary-region MM point charges according to the principles of electronegativity equalization and charge conservation until the charge distributions in both the QM subsystem and the polarizable region of the MM subsystem converge. In particular, we implemented three literature parametrizations of electronegativity equalization: the original electronegativity equalization method (EEM) by Mortier and co-workers, the charge equalization (QEq) method proposed by Rappé and Goddard, and a modified version of the QEq method by Bakowies and Thiel. The PBRC and PBRCD schemes were tested by calculating proton affinities for small organic compounds and capped amino acids. As compared to full-QM calculations, the PBRC and PBRCD schemes produced more accurate proton affinities, on average, than the original RC and RCD methods; the mean unsigned error in proton affinities is reduced from about 5 kcal/mol to 3 kcal/mol with little change in geometry. The improvement is encouraging and illustrates the importance of mutual polarization of the QM and MM subsystems in treating reactions where noticeable charge transfer occurs in the QM subsystem.

Quantification of Predictability in Clinical Trials Using Block Randomization

In block-randomized clinical trials where the treatments can be identified by their appearance or effects, knowledge of the length and composition of the blocks enables prediction of the nature of one or more treatments at the end of a block and may introduce a selection bias. Matts and Lachin (1) have quantified "predictability with certainty" for two-arm trials with balanced randomization. In this paper, we provide a formula which can be used for measuring predictability in other situations: trials with three or more arms, and trials with unbalanced treatment allocation. In addition, we have provided tables of values for predictability according to common lengths and composition. Examples of results obtained in common situations are provided. The importance of bias associated with predictability and the methods to limit it are discussed, and practical recommendations are provided.

The Good, the Bad, and the Ugly in Global Forest Politics

Tropical Forests, International Jungle: The Underside of Global Ecopolitics. By Marie-Claude Smouts. Translated from the French by Cynthia Schoch. New York: Palgrave Macmillan, 2003. 280 pp., $59.95 (ISBN: 1-4039-6203-0). Marie-Claude Smouts's Tropical Forests, International Jungle represents an interesting contribution to the growing literature on international environmental politics in the field of international relations (IR), as well as to our understanding of global forest politics—one of the more neglected topics in the field. Critical of traditional IR approaches, which she deems too abstract and excessively focused on the concepts of state, power, and sovereignty, Smouts seeks to demonstrate the value of applying a sociological approach to environmental politics. Her research centers on empirical investigations of transnational patterns of action that shape the emergence of global discourses, and the ethical and political implications of rules and instruments created at the global level and forced upon local actors. Although not explicitly acknowledged, Tropical Forests, International Jungle is part of the larger constructivist challenge to mainstream international relations. Unfortunately, because Smouts does not elaborate on current debates in the field, her study falls short with respect to the theoretical contribution it claims to make. Those who have followed this arena or have worked with the organizations that appear in the book may also find the sometimes cynical and unbalanced treatment of these protagonists regrettable. Nonetheless, Smouts provides captivating insights into key facets of global forest politics, thanks primarily to her fieldwork. Tropical Forests, International Jungle correctly asserts that, despite today's technological capabilities and long-running international dialogues, we have neither adequate knowledge of the quantity and quality of tropical forests, …

Love's labor's lost? the disutility of work and work avoidance in the economic analysis of labor supply

This paper explores the origins and evolution of the concept of the disutility of work. The original formulation of this concept developed by Stanley Jevons and by Alfred Marshall recognizes the variability of work motives stressing the effects of both the quantity and quality of work on labor supply. Subsequent writers, notably Lionel Robbins, and later Gary Becker, focus on the opportunity cost of work time, to the neglect of the content of work. These writers lose sight of the influence of the nature of work on the supply of labor. Contemporary research on the economics of labor supply, while accepting the presence of agency problems surrounding the enforcement of the labor contract, continues to consign the determinants of work motives to a black box. The new emphasis on the problem of “shirking” by workers, in particular, offers an unbalanced treatment of the causes and consequences of work resistance.

General balance, large data sets and extensions to unbalanced treatment structures

General balance defines an important class of designs covering virtually all the traditional experimental designs and, in particular, those with several error terms. In these designs the block terms are mutually orthogonal, the treatment terms are also mutually orthogonal, and the contrasts of each treatment term have equal efficiency factors in each of the strata where they are estimated. Generally balanced designs can efficiently be analysed by an algorithm which involves a series of sweep operations for each stratum. Each sweep estimates the effects of a treatment term (by its means divided by the efficiency factor), and subtracts them from the current working vector which then becomes the working vector for the next sweep. Workspace requirements are considerably less than those of multiple-regression style algorithms, so the algorithm has great advantages particularly with large treatment models. With large data sets, however, it may be more difficult to fulfill all the conditions of general balance. One possibility is to retain orthogonal block structure, but allow unbalanced treatment structures. It is shown that the algorithm can successfully be adapted to this situation, but it now requires an iterative sequence of sweeps to fit the treatment model in each stratum.

Evaluation of a plastic shoe

Hoof-related lameness in horses is common; however, very few critical studies have been performed to evaluate the ability of different shoes to reduce lameness. Dr. Chris Kawcak, with Drs. David Frisbie and Wayne McIlwraith, worked with Val Perino, an MS student, to develop a project intended to compare horses that were unshod, shod with steel shoes, and shod with plastic shoes (Dynamix shoes) in both balanced and controlled, unbalanced states. The specific aims of the study were to compare clinical lameness, ground reaction force, and hoof strain in unshod, traditionally shod, and Dynamix shod horses in both balanced and controlled, unbalanced states. This led to the hypothesis that Dynamix shod horses would have less clinical lameness, increased ground reaction force, and less hoof strain than unshod and traditionally shod horses. Six horses, ages 3 to 5 years, were chosen for the study and treated in accordance with ACUC protocol. The first groups of measurements were on hooves that were trimmed for normal balance. The left front hooves of all horses were then trimmed in an unbalanced manner starting on week 18. Lameness was graded in each horse at a jog according to a subjective lameness scoring system. Each horse was also jogged across a Tekscan sensor mat at a controlled speed. The force, pressure, and contact area were determined for each hoof. Rosette strain gauges were also applied to the prepared hoof at the medial and lateral quarters in both parallel and perpendicular fashion. Data were analyzed by using a mixed model analysis of variance and least squares mean when appropriate. A P value less than .05 was considered significant. Horses were significantly more lame when they wore Dynamix shoes without the clips compared with clips. The controlled, unbalanced model induced a level of lameness that was appropriate for seeing the effects of treatment. It was also found that the horses were less lame in Dynamix shoes compared with when they were unshod in both balanced and unbalanced states. Ground reaction force was highest in the Dynamix treatment group compared with the traditionally shod group. However, the force was higher in the unshod and Dynamix treatment groups when the hooves were unbalanced, which does not correlate with the increased lameness seen when the hooves were unbalanced. The controlled, unbalanced treatment significantly reduced lateral coronary band compression as seen by a reduction in lateral transverse hoof strain. In conclusion, the Dynamix shoe appears to reduce lameness in both balanced and unbalanced states; however, the clips appear to be an essential component of the design. This is the first time that the Tekscan technology has been used to assess abnormal hoof conformation and the investigators are currently planning to further evaluate the Tekscan system against a force plate to determine the meaning of these data. (From Colorado State University Orthopaedic Researach Center Laboratory Report. The complete study was published as: Perino, V MS Thesis. Colorado State University. 2002.) Copyright 2002, Elsevier Science (USA). All rights reserved. 0737-0806/02/2208-0008$35.00/0 doi:10.1053/jevs.2002.37110 Fig 1. (A) Natural Balance shoe, (B) Egg Bar shoe, and (C) Dynamix shoe.

Breast cancer: Post-mastectomy radiotherapy: recommended standards

The local recurrence rate after mastectomy in breast cancer patients varies significantly in reported series; in some publications from 2% to even more than 50% at 10 years. The reasons for these differences can be found in patient selection and the surgical method and technical skills of the surgeon. For example, a low recurrence percentage can be obtained by combining a good surgical procedure with the exclusion of patients for radical mastectomy by following strict inoperability criteria. For this purpose, the following criteria are often used: fixation of the tumour and/or lymph nodes to the chest wall, inflammatory breast cancer, and in some institutes a positive axillary apex biopsy. In 1949 Ralston Paterson and colleagues in Manchester started probably the first randomized clinical trial in the world investigating the potential of radiotherapy in improving local control and indirectly survival [1]. They randomized patients after mastectomy between no radiotherapy and post-mastectomy radiotherapy. For this purpose 1461 patients were entered in this trial. He and his colleagues demonstrated that radiotherapy was able to reduce significantly the amount of local recurrences thereby preventing patients dying from symptoms of uncontrolled local disease. Unfortunately long term follow up showed that the potential gain in survival was diminished by an excess of radiotherapy-related cardiovascular complications. It would be unfair to criticize the trial design according to current standards and the radiation technique used but a few remarks should be made here. For example, the randomization was based on the patient's date of birth (odd or even), so the surgeon would know beforehand in which arm the patient would be randomized. He may have therefore decided not to select patients for the trial if they had a high risk of local recurrence knowing that they would be randomized to no further treatment. Instead he may have referred these patients for radiotherapy, leading to unbalanced treatment arms. The major reason for the excess of cardiovascular deaths seen in this trial was the equipment available at that time. The patients were treated with orthovoltage equipment using a technique that delivered a high dose to a large part of the heart with higher fraction doses. A reduction of the local recurrence rate, by a factor of 0.6, by post-mastectomy radiotherapy has now been confirmed by many trials. It took until recently for it to be demonstrated that improvement in local control could result in about 10% improved survival rate [2-4]. These results became available with the publication of the long term follow up data from a few major trials started after 1975. These trials have shown a gain that can be reached by careful selection of high-risk patients for radiotherapy and through the execution of meticulous radiotherapy techniques, avoiding over dosage of radiation to the heart. The impact of improved local control on the survival rate shown by these trials suggests that distant metastases may arise from recurrent local disease, stressing the need for adequate local treatment.

Excitation energies and oscillator strengths of Ca I using multireference many-body perturbation theory

Atomic transition lines of neutral calcium were first found in solar spectrum as early as the middle of the 19th century, when the 4227-A line was identified along with the famous singly ionized H and K lines @1#. Neutral calcium lines have also been observed in all types of stellar and interstellar spectra, such as late-type dwarf stars. The crude abundance of Ca I (l56717.7 A ) has been observed in Am binaries@2#. To confirm those identifications and to find new lines, one has to depend on atomic experimental data or computational data based on theoretical models of the calcium atom. The abundances of neutral calcium in these astronomical bodies depend on the oscillator strengths of those lines, which come from the excitation energies of various levels and transition moments among those levels. The difficulty in accurately estimating transition energies and oscillator strengths of neutral calcium atom arises mainly due to the following reasons: ~a! The precise computation of transition energies and oscillator strengths requires a balanced description of the ground and excited states. ~b! The use of an inadequate basis leads to difficulties in describing the excited states and an unbalanced treatment of dynamical correlation and polarization effects. The problems due to basis set inadequacy can be removed partially by enlarging the basis for small and moderate-sized atomic and molecular systems. Here, the size extensivity @3# of the theory plays an important role in handling the proper treatment of electron correlation, and in that way it properly treats the differential correlation energies of the interacting ~initial and final states! zeroth-order states. It ensures that the state energies scale linearly with the number of electrons in a rigorous way. The accuracy of the computed excitation energy depends mostly upon the quality of the unoccupied valence orbitals in which excitation occurs. The traditional choice of some unoccupied valence orbitals from a ground-state selfconsistent-field ~SCF! computation introduces V N orbitals that are best suited for describing negative ions, and not lowlying excited states. Thus the valence orbitals, those that are not occupied in the ground-state SCF, should be taken as more representative orbitals suitable for excited states. One possible choice emerges from the restricted single excitation configuration interaction procedure@4#, where excitations are only permitted from the highest occupied orbitals. A simpler and often equivalent approaches involves using improved virtual orbitals ~IVO’s !@ 5 #in the H v valence space or reference space. Here the IVO’s are generated by single orbital SCF optimization in which the Fock operator is defined by promoting an electron from the highest occupied orbital to the orbital being optimized, while all the previously determined orbitals are kept frozen. Alternatively this can be accomplished by a unitary transformation @6#. The IVO orbital energies obtained in this way are lower than those evaluated from the traditional SCF procedure due to the absence of an extra Coulomb operator in the former procedure. For example, in a neutral calcium atom H v calculation, the twoorbital (4 s,4p) minimal reference space is produced by the sequence

Nitrate and phosphate uptake by Agropyron desertorum and Artemisia tridentata from soil patches with balanced and unbalanced nitrate and phosphate supply

To test the ability of plants to integrate small‐scale imbalances in soil nitrate and phosphate patches, plant growth and acquisition of nitrate and phosphate were measured for the perennial grass Agropyron desertorum (Fisch. ex Link) Schult. and the shrub Artemisia tridentata Nutt. ssp. vaseyana (Rydb.) Beetle in soil where the principal supply of nitrate and phosphate came from two enriched patches. The soil was calcareous loamy‐skeletal Typic Haploxerolls. These patches were applied in two treatments: either nitrate and phosphate were applied in both patches (balanced treatment) or one patch contained only nitrate and the other only phosphate (unbalanced treatment). The same total quantity of nutrients was applied in both treatments and these included 15N and 32P tracers. The plants were in large pots in open field conditions. There were no significant differences in total biomass production and nitrogen concentration between the two treatments, indicating that both species had the physiological ability to integrate soil nutrient resources. Artemisia was able to acquire more phosphate in the unbalanced treatment, probably due to the high local solution phosphate concentration. Generally Artemisia acquired more N and P than did Agropyron.

Dose finding strategies involving interim analyses and unbalanced treatment allocation.

Dose finding studies usually require the application of multiple test procedures (MTP). A variety of procedures is available for data analyses. Focusing on testing only subset hypotheses of interest requires only limited alpha-adjustment. Specific strategies based on MTP, in particular closed test procedures, which also consider dropping dose groups and unequal group sizes, lead to substantial reduction in total sample size. Of course, strategies discussed here can be extended to comparisons of more than five groups, and they may be generalized to cover equivalence tests, too. For example, one may want to demonstrate therapeutical equivalence of two dose regimens like b.i.d. and o.d. administrations of the drug.

Spatial Nature of Randomization and Its Effect on the Outcome of Field Experiments

AbstractMany sites used for field trials exhibit a spatially‐dependent variance structure in that nearby observations are autocorrelated. This may affect treatment comparisons made at unequal distances. This study investigated (i) the probabilistic nature of randomization with respect to spatial distances in randomized complete block (RCB) designs and (ii) the effect of spatially unbalanced designs on the outcome of field experiments. The mean distance of treatment comparison increases linearly with the number of treatments in the experiment. The lack of spatial balance also increases and is inversely related to the number of replications. This may result in increases in Type II errors for short‐distance treatment contrasts and increases in Type I errors for long‐distance contrasts. Evaluation of two experimental RCB designs involving four and nine treatments and four replications showed that the randomization process does not ensure spatial balance. Two simulated experiments, each using 50 randomizations based on the Mercer and Hall data showed no adverse effect from spatially unbalanced treatment comparisons if the underlying variance structure is random, but significant effects if spatial autocorrelation is present. Expected variances for long‐distance comparisons (5.6% of all comparisons) were 51% higher than the error term resulting in tests of treatment differences at ɑ = 0.05 to actually be conducted at the 0.09 error level. Alternative design and analysis methods that ensure spatially balanced treatment comparisons are discussed.

Tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of protocol 83-08 of the radiation therapy oncology group

A prospective, centrally randomized Phase I/II trial of hyperfractionation in definitive radiation therapy for locally advanced squamous and transitional cell carcinoma of the bladder was conducted by the Radiation Therapy Oncology Group (RTOG) from April 1983 through June 1986. Patients with T3–4 and T2 N+ (AJC) histologically-confirmed cancer of the bladder received twice daily radiation therapy with 1.2 Gy per fraction and a minimum of 4 hr between fractions. All patients received a whole pelvic total dose of 50.4 Gy: Total doses to reduced volumes were 60.0 Gy, 64.8 Gy, or 69.6 Gy. Of 54 patients entered, 50 were eligible. An unbalanced treatment assignment was used: Nine patients received 60.0 Gy, 15 patients received 64.8 Gy and 26 received 69.6 Gy. Performance status (Karnofsky) was 90–100 in 72% of patients and 92% had transitional carcinoma. Eighty percent of tumors were T3 or T4. Observation of at least 18 months was available for 26 patients. Grade 3 acute reactions (within 90 days) were reported in eight patients (one at 60.0 Gy, three at 64.8 Gy and four at 69.6 Gy). Five patients experienced a total of seven major late effects—four Grade 3 and three Grade 4. The cumulative probability of Grade 3 and 4 late complications of treatment for the 46 patients at risk for late complications was 5% ± 3% at 6 months, 7% ± 4% at 12 months, and 10% ± 5% at 18 and 24 months. The cumulative probability of Grade 3 or 4 late complications for patients who received a total dose of 69.6 Gy was 5% ± 4% at 6 and 12 months and 11% ± 8% at 18 and 24 months. Only one patient who experienced major late effects was also reported to have major acute reactions. Comparisons of survival of patients treated in the current study with those who received 60 Gy in 30 fractions in 6 weeks in RTOG Protocol 71-04, did not suggest any deleterious effects from hyperfractionated radiation therapy to the pelvis. The normal pelvic tissues tolerated hyperfractionated radiation therapy sufficiently well to justify exploring it, alone and with brachytherapy, in other pelvic tumors.

Seasonality and the Name of the Nile

of ancient Egypt. The surviving records written as well as representational fairly pulsate with the insistences of time; yet the Egyptological literature offers an unbalanced treatment of the subject. Aside from a sizable bibliography on calendrical/chronological issues and on grammatical temporality all quite important, to be surecomparatively little attention has been accorded to the economic and social aspects of time in the daily lives of Egyptians, certainly nothing to rival the amount of ink and paper that has been expended on the Egyptian concept of eternity.1 The stress on eternity is not without some irony in the sense that the subject has more to do with timelessness; but even that topic has value beyond its broader philosophical implications in that it helps us to understand what it was about experienced time the Egyptians sought to escape, namely time's monstrous offspring, change. Timelessness, moreover, includes basic ideas and modes of discourse about time, else we would be unable to talk about it, much less conceive of it. This view smacks of a truism, of course, but that fact makes it all the more surprising that scholars have allowed the seemingly interminable discussions of eternity (including the host of artful translations of the basic Egyptian words for eternity) to dominate the ways in which we approach temporal issues. The consideration of the socio-economic aspects of time alluded to earlier requires prior attention to some general features of Egyptian temporal perception. Among these would be such topics as the definition of event; the location of events in time, event relationships; interval; sequence; duration; periodicity and the like. The present essay, part of a more extensive examination of time in ancient Egypt,2 will be limited to a particular aspect of periodicity, namely seasonality. By periodicity, I mean regularly recurring events, phenomena, or circumstances. Implicit as well is the notion that such recurrences are, to one degree or another, significant, for they help to understand the phenomenal world. In the last section of this paper, I will make some observations on the name of the most reliably recurrent natural phenomenon, the Nile.3 Some caveats are in order at the outset. For one

The bias coin design

In clinical research with small sample size, problems can arise in allocating subjects into various treatment groups when they are accessioned into a study over time. The Biased Coin Design (BCD) was designed to overcome the problems of biased or unbalanced treatment groups, while ensuring the advantages of complete randomization. The BCD is discussed, and an example of its use in clinical research is given.

Compensatory Photosynthetic Responses of Three African Graminoids to Different Fertilization, Watering, and Clipping Regimes

Three C4 graminoids, Kyllinga nervosa, Themeda triandra, and Hyparrhenia filipendula, were grown in unbalanced factorial treatment designs of clipping height, clipping frequency, watering frequency, and nitrogen availability for periods equivalent to one growing season, after which gas exchange was measured on all plants. Clipped plants in all three species had higher photosynthetic rates, but the percentage of stimulation was least in T. triandra. Stimulation of photosynthesis may have been caused by increased stomatal opening.