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PubMed1995

Sample size estimation for clinicians.

The purpose of this paper is to describe the importance of an adequate sample size in clinical research and to enable clinicians to estimate their own sample size requirements for the more common types of studies (comparison of two means or two proportions). Four pieces of information are required to determine sample size: the desired level of statistical power, the level of statistical significance, the variability of the data, and the smallest difference between the study groups that is considered to be of clinical significance. Worked examples from the literature are used to illustrate how clinicians may easily do their own sample size calculations using published tables or available computer software, or both. The consideration of sample size and power during the planning stages of clinical research is crucial to the subsequent interpretation of study results, especially if the study is negative, and yet this point is often neglected in the medical literature. Attention to these simple guidelines will help ensure that research results lead to valid conclusions.

Biometry↗
PubMed2004

Multivariate linkage analysis of blood pressure and body mass index.

Multivariate linkage analyses of correlated traits provide greater statistical power to identify genetic loci with effects too small to be detected in single trait analyses. We conducted genomewide multivariate analyses of systolic BP, diastolic BP, and body mass index (BMI) in 1,848 non-Hispanic white subjects (968 females, 880 males) from 279 multigenerational pedigrees from Rochester, Minnesota. Blood pressure was measured by random zero sphygmomanometer; body mass index was calculated from measurements of height and weight; and genotypes were measured at 520 microsatellite marker loci distributed across the 22 autosomes. Univariate linkage analyses demonstrated tentative evidence of linkage (defined by univariate LOD scores of 1.30-1.99) for diastolic BP on chromosome 18 and for BMI on chromosomes 3, 10, and 18. Bivariate linkage analyses showed tentative evidence of linkage (defined by bivariate LOD scores of 2.06-2.86) for systolic and diastolic BP on chromosome 14 and for either measure of BP and BMI on chromosomes 2, 3, 10, and 18; and suggestive evidence of linkage (defined by bivariate LOD scores of 2.87-3.99) for either measure of BP and BMI on chromosomes 10 and chromosome 15. Trivariate linkage analyses of systolic and diastolic BP and BMI provided evidence of a region influencing all three traits on chromosome 10, where the trivariate LOD score rose to a maximum value of 4.09 (at 144 cM, P=0.0007), and possibly on chromosome 2, where it rose to a maximum value of 2.80 (at 77 cM, P=0.0075). For genomewide linkage analyses to succeed in localizing genes influencing BP, it may be advantageous to exploit the greater statistical power of multivariate linkage analyses to identify loci with pleiotropic effects on correlated traits.

Adult↗
PubMed2001

Interventions for herpes simplex virus epithelial keratitis.

BACKGROUND: Many clinical trials have been performed on the acute treatment of dendritic epithelial keratitis. Surveys of antiviral pharmacology and of herpes simplex virus eye disease have evaluated different commercially available agents, but a systematic review of all comparative clinical studies has not previously been undertaken. OBJECTIVES: The objective of this review is to compare the effects of various treatments for dendritic or geographic herpes simplex virus epithelial keratitis. SEARCH STRATEGY: Sources searched for relevant studies were the Cochrane Eyes and Vision Group specialized register, The Cochrane Controlled Trials Register - CENTRAL, MEDLINE, EMBASE, Index Medicus, Excerpta Medica Ophthalmology, reference lists of primary reports, review articles, and corneal textbooks and conference proceedings pertaining to ocular virology. SELECTION CRITERIA: This review includes comparative clinical trials that assessed oral or topical ophthalmic antiviral agents, or physical or chemical debridement in people with active epithelial keratitis. DATA COLLECTION AND ANALYSIS: The reviewer extracted data and assessed trial quality. Interventions were compared by the proportions of participants healed at seven days and at fourteen days after trial enrollment. MAIN RESULTS: This review includes data from 96 trials which randomised a total of 4991 participants. Compared to idoxuridine, the topical application of vidarabine, trifluridine, or acyclovir generally resulted in a significantly greater proportion of participants healing within one week of treatment. Among these three antiviral agents, no treatment emerged as significantly better for the therapy of dendritic epithelial keratitis. Insufficient placebo-controlled studies were available to assess debridement and other physical and physicochemical methods of treatment. Interferon monotherapy had a slight beneficial effect on dendritic epithelial keratitis, but not better than other antiviral agents, and was useful with debridement. REVIEWER'S CONCLUSIONS: Currently available and investigational antiviral agents are effective and nearly equivalent, but the combination of an antiviral nucleoside and interferon seems to speed healing. Future trials of the acute treatment of herpes simplex virus epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response.

Administration, Oral↗
PubMed2005

The bioequivalence of highly variable drugs and drug products.

'Highly variable drugs' have been defined as those drugs for which the within-subject variability (WSV) equals or exceeds 30% of the maximum concentration (Cmax) and/or the area under the concentration versus time curve (AUC). Despite the fact that highly variable drugs are generally safe with flat dose response curves, the bioequivalence of their formulations is a problem because the high variability means that large numbers of subjects are required to give adequate statistical power. Highly variable drug products are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem rather than high innate WSV of the drug itself. A further problem caused by high variability is that a subset of the population may respond differently to the two formulations producing a significant subject x formulation interaction. Practical examples are shown using replicate designs. The methods proposed to deal with the problems posed by highly variable drugs include: (i) Drug regulatory jurisdictions states that the 90% confidence interval (90% CI) around the test to reference geometric mean ratio (GMR) is required to fit with bioequivalence acceptance limits of 0.8 - 1.25 for both Cmax and AUC. The WSV for single point estimation of Cmax is often greater than that for AUC. One strategy therefore is not to require a 90% CI for Cmax of drugs that do not exhibit a toxicity associated with Cmax and merely require the GMR to fall within the acceptance limits. (ii) To arbitrarily broaden the bioequivalence acceptance limits. For example, to permit a sponsor to justify the use of wider limits e.g the 90% CI around the GMR of Cmax values might be required to fit within acceptance limits of 0.75 - 1.33 or even 0.70 - 1.42. (iii) A more systematic approach would be to broaden the acceptance limits by scaling to either the residual variance from a 2-period design or to the WSV of the reference product in a replicate design. Subsequent evaluations of scaling procedures have demonstrated that smaller numbers of subjects are required for bioequivalence studies on formulations of highly variable drugs. A disadvantage of scaling is that the method is less sensitive to differences between the means compared with unscaled treatment, such that the GMR may prove to be unacceptably low or high. This possibility has let to a suggestion that the GMR must fall within acceptance limits of 0.8 - 1.25 in scaled treatments. (iv) A similar method is to scale the metric rather than the acceptance limits. This method was proposed by the United States' Food and Drug Administration in the context of Individual bioequivalence, but may also be applied (v) to average bioequivalence. (vi) To carry out bioequivalence studies at steady state whenever a multiple dose regimen is ethically acceptable for healthy volunteers. This solution is based on the observation that high variability in a single dose study tends to be dampened at steady state, thus increasing statistical power. Drug regulators have not favored this approach on the grounds that bioequivalence testing should be based on the most discriminating test possible. (vii) Finally the use of metabolite data has been proposed since in many (but by no means all) cases, metabolite is less highly variable than that of the parent drug. This subject remains controversial except when the administered substance is a prodrug which converted by metabolism into the active drug.

Area Under Curve↗
PubMed2003

Power calculations for survival analyses via Monte Carlo estimation.

BACKGROUND: Power calculations can be a useful step in the design of epidemiologic studies. For occupational and environmental cohort studies, however, the calculation of statistical power has been difficult because researchers are often interested in situations where exposure assignment is time-dependent, and in research questions that pertain to cumulative exposure-mortality trends evaluated with statistical methods for survival analysis. These conditions are not easily accommodated by available software or published formulas for power calculation. METHODS: Monte Carlo methods can be used to estimate statistical power for survival analyses. Simple computer programs are presented to illustrate this approach. RESULTS: We show that, for the simple case of a randomized clinical trial involving a dichotomous exposure, the results of power calculations derived via this Monte Carlo approach conform to values derived using a previously published formula. We then illustrate how the Monte Carlo approach may be extended to obtain estimates of statistical power for analyses of cumulative exposure-mortality trends under conditions more typical of occupational cohort studies. CONCLUSIONS: The Monte Carlo approach provides a way to perform power calculations for a wide range of study conditions. The approach illustrated in this study should simplify the task of calculating power for survival analyses, particularly in epidemiologic research on occupational cohorts.

Epidemiologic Research Design↗
PubMed1998

Influence of protein structure databases on the predictive power of statistical pair potentials.

A long standing goal in protein structure studies is the development of reliable energy functions that can be used both to verify protein models derived from experimental constraints as well as for theoretical protein folding and inverse folding computer experiments. In that respect, knowledge-based statistical pair potentials have attracted considerable interests recently mainly because they include the essential features of protein structures as well as solvent effects at a low computing cost. However, the basis on which statistical potentials are derived have been questioned. In this paper, we investigate statistical pair potentials derived from protein three-dimensional structures, addressing in particular questions related to the form of these potentials, as well as to the content of the database from which they are derived. We have shown that statistical pair potentials depend on the size of the proteins included in the database, and that this dependence can be reduced by considering only pairs of residue close in space (i.e., with a cutoff of 8 A). We have shown also that statistical potentials carry a memory of the quality of the database in terms of the amount and diversity of secondary structure it contains. We find, for example, that potentials derived from a database containing alpha-proteins will only perform best on alpha-proteins in fold recognition computer experiments. We believe that this is an overall weakness of these potentials, which must be kept in mind when constructing a database.

Chemical Phenomena↗
PubMed1991

A new family of powerful multivariate statistical sequence analysis techniques.

A novel multivariate statistical approach is presented for extracting and exploiting intrinsic information present in our ever-growing sequence data banks. The information extraction from the sequences avoids the pitfalls of intersequence alignment by analyzing secondary invariant functions derived from the sequences in the data bank rather than the sequences themselves. Such typical invariant function is a 20 x 20 histogram of occurrences of amino acid pairs in a given sequence or fragment thereof. To illustrate the potential of the approach an analysis of 10,000 protein sequences from the National Biomedical Research Foundation Protein Identification Resource is presented, whose analysis already reveals great biological detail. For example, zeta-hemoglobin is found to lie close to amphibian and fish chi-hemoglobin which, in turn, is an important clue to the physiological function of this mammalian early embryonic hemoglobin. The multivariate statistical framework presented unifies such apparently unrelated issues as phylogenetic comparisons between a set of sequences and distance matrices between the constituents of the biological sequences. The Multivariate Statistical Sequence Analysis (MSSA) principles can be used for a wide spectrum of sequence analysis problems such as: assignment of family memberships to new sequences, validation of new incoming sequences to be entered into the database, prediction of structure from sequence, discrimination of coding from non-coding DNA regions, and automatic generation of an atlas of protein or DNA sequences. The MSSA techniques represent a self-contained approach to learning continuously and automatically from the growing stream of new sequences. The MSSA approach is particularly likely to play a significant role in major sequencing efforts such as the human genome project.

Amino Acid Sequence↗
PubMed1998

A randomized clinical trial of the nonsteroidal eyedrop diclofenac after strabismus surgery.

OBJECTIVE: This study aimed to compare the anti-inflammatory and analgesic effects of topical diclofenac sodium 0.1% (Voltaren) with prednisolone sodium phosphate 1% ophthalmic solution after strabismus surgery. DESIGN: A prospective, double-masked, randomized, two-center clinical trial. PARTICIPANTS: Eighty eyes of 52 patients undergoing strabismus surgery were examined. INTERVENTION: For 1 week after surgery, the eye that was operated on received one drop of either diclofenac or prednisolone four times a day. MAIN OUTCOME MEASURES: The diclofenac- and prednisolone-treated eyes were compared on postoperative days 3 and 7 with respect to signs of inflammation (e.g., erythema, edema, discharge), patient comfort, and conjunctival incisional healing. RESULTS: On postoperative day 7, in eyes that received prednisolone, the conjunctival defects were larger (P = 0.004) and more frequent (P = 0.02). For all subjects, despite adequate statistical power, there was no statistically significant difference in inflammatory scores between eyes that received diclofenac or prednisolone. In cases of bilateral surgery, however, there was less postoperative erythema and edema in the diclofenac-treated eyes. CONCLUSIONS: In the first week after strabismus surgery, topical diclofenac proved at least as effective as prednisolone in controlling inflammation and discomfort with less delay in incisional wound healing. Topical diclofenac, a nonsteroidal anti-inflammatory agent, may be considered for use after strabismus surgery in place of corticosteroids.

Administration, Topical↗
PubMed1995

Pre mortem analysis of lung injury and lung function in oxygen toxic rabbits.

OBJECTIVES: To determine whether respiratory system mechanics measurements could detect lung injury in oxygen toxic rabbits before clinical deterioration. To determine whether respiratory system mechanics measurements, using a power analysis, have the statistical power to detect significant reductions in hyperoxic lung injury due to an intervention when compared with traditional post mortem measurements of lung injury, extravascular lung water, and bronchoalveolar lavage protein concentration. DESIGN: Prospective, controlled study. SETTING: Institutional animal laboratories. SUBJECTS: Adult New Zealand white rabbits. INTERVENTIONS: Spontaneously breathing adult New Zealand white rabbits were exposed continuously to either > 95% oxygen or room air. MEASUREMENTS AND MAIN RESULTS: We measured arterial pH, blood gas tensions, and respiratory system mechanics in rabbits twice, both before exposure to > 95% oxygen, and after the rabbits developed symptoms of mild lung dysfunction. After the second set of respiratory system mechanics measurements, we measured extravascular lung water and bronchoalveolar lavage protein concentration in the hyperoxia-exposed rabbits and compared the values with those values obtained in animals that breathed room air only. Our hyperoxia-exposed rabbits developed symptoms of mild respiratory impairment at 69 +/- 2 hrs. In these hyperoxia-exposed rabbits, measurements of static compliance, quasi-static compliance and resistance all changed significantly (p < .05) when compared with baseline measurements. Functional residual capacity and arterial blood gas values did not change significantly. Furthermore, assuming that an intervention reduced hyperoxic lung injury by a given amount, we performed a power analysis and found that the measurement of static compliance had at least equivalent power to detect a reduction in lung injury from an intervention when compared with measurement of extravascular lung water and bronchoalveolar lavage protein concentration. CONCLUSIONS: Measurements of respiratory system mechanics can detect lung injury in hyperoxic rabbits before the onset of severe clinical deterioration or death. Furthermore, measurement of static compliance of the respiratory system is likely to be a powerful tool to detect a reduction in lung injury produced by an intervention.

Airway Resistance↗
PubMed2003

Brain tissue oxygen monitoring for assessment of autoregulation: preliminary results suggest a new hypothesis.

Brain tissue oxygen monitoring (P(ti)O2 (Neurotrend, Codman, Germany) was employed in addition to standard intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring in seven patients with severe neuronal damage of heterogeneous etiology. The correlation between P(ti)O2 changes and CPP fluctuations during periods of 30 minutes were analyzed, when CPP was above 70 mmHg and lower than 100 mmHg. A new ratio, the CPP-oxygen-reactivity (COR) index was calculated as COR=delta p(ti)O2 %/delta CPP%. The patient COR values were compared to those found in the brain of six noninjured anesthetized piglets. The analysis was performed to determine the significance of synchronous fluctuations of CPP and P(ti)O2, when CPP is above the lower threshold of autoregulation. The correlation between CPP variations and p(ti)O2 variations was found to be strong (R(mean)) = 0.74 +/- 0.17) in the patients and was weak in the uninjured animals (R(mean)) =0.38 +/- 0.43). The COR (mean) was 2.05 +/- 0.57 in patients and 0.78 +/- 0.6 in the animals. In the injured brain of our patients, we observed an unexpectedly close correlation between P(ti)O2 and CPP variations when CPP levels were within a therapeutically targeted range (70 to 100 mmHg). In a porcine model, we could not find this relationship in the noninjured brain. We speculate that an increased COR might be indicative for an impaired local pressure autoregulation. The preliminary data suggest that COR values above "1" might be pathologic. However, the reported sample sizes are too small to provide sufficient statistical power to justify inferential statistical analyses. As such, results are presented with descriptive statistics only, and should be regarded as a hypothesis.

Algorithms↗
PubMed2006

Plasma anhydro-D-glucitol (1,5-AG) as an indicator of hyperglycaemic excursions in pregnant women with diabetes.

AIMS: To evaluate the use of the plasma 1,5-anhydro-d-glucitol (1,5-AG) level as a possible marker for glucose excursions in pregnant women with diabetes. METHODS: The study group consisted of 55 pregnant women with diabetes (gestational diabetes mellitus-GDM, n = 28 or pre-gestational diabetes mellitus -PGDM, n = 27), without hepatic or renal insufficiency, gestational age range 5-38 weeks. In each patient, 24-h glucose profile, glycated haemoglobin and 1,5-AG plasma levels were measured. Mean blood glucose (MBG) and M-value (by Schlichtkrull) were calculated. MBG, M-value and maximal daily glycaemia (MxG) were used as indexes of daily glycaemic excursions. RESULTS: A significant correlation was found between the 1,5-AG plasma level and MxG [r = (-0.3)] and between the 1,5-AG level and M-value [r = (-0.36)]. There was no association between the 1,5-AG level and gestational age. Multivariate regression analysis, with 24-h glucose profile, gestational age and MxG as independent variables, showed that MxG was the main parameter determining the 1,5-AG plasma level [beta = (-0.68)]. The M-value, the coefficient of glucose fluctuations, also determined the 1,5-AG level but with lower statistical power [beta = (0.41)]. No statistical differences were found in the group with HbA(1c) < 6% or > 6% for 1,5-AG and M-value, while MBG was higher in poorly controlled patients (HbA(1c) > 6%). CONCLUSIONS: The plasma 1,5-AG level may be a useful marker of daily glucose excursion in pregnant women with diabetes, as an adjunct to HbA(1c) monitoring.

Adolescent↗
PubMed2004

Whole genome DNA copy number changes identified by high density oligonucleotide arrays.

Changes in DNA copy number are one of the hallmarks of the genetic instability common to most human cancers. Previous microarray-based methods have been used to identify chromosomal gains and losses; however, they are unable to genotype alleles at the level of single nucleotide polymorphisms (SNPs). Here we describe a novel algorithm that uses a recently developed high-density oligonucleotide array-based SNP genotyping method, whole genome sampling analysis (WGSA), to identify genome-wide chromosomal gains and losses at high resolution. WGSA simultaneously genotypes over 10,000 SNPs by allele-specific hybridisation to perfect match (PM) and mismatch (MM) probes synthesised on a single array. The copy number algorithm jointly uses PM intensity and discrimination ratios between paired PM and MM intensity values to identify and estimate genetic copy number changes. Values from an experimental sample are compared with SNP-specific distributions derived from a reference set containing over 100 normal individuals to gain statistical power. Genomic regions with statistically significant copy number changes can be identified using both single point analysis and contiguous point analysis of SNP intensities. We identified multiple regions of amplification and deletion using a panel of human breast cancer cell lines. We verified these results using an independent method based on quantitative polymerase chain reaction and found that our approach is both sensitive and specific and can tolerate samples which contain a mixture of both tumour and normal DNA. In addition, by using known allele frequencies from the reference set, statistically significant genomic intervals can be identified containing contiguous stretches of homozygous markers, potentially allowing the detection of regions undergoing loss of heterozygosity (LOH) without the need for a matched normal control sample. The coupling of LOH analysis, via SNP genotyping, with copy number estimations using a single array provides additional insight into the structure of genomic alterations. With mean and median inter-SNP euchromatin distances of 244 kilobases (kb) and 119 kb, respectively, this method affords a resolution that is not easily achievable with non-oligonucleotide-based experimental approaches.

Cell Line, Tumor↗