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P-values and confidence intervals: two sides of the same unsatisfactory coin.

For both P-values and confidence intervals, an alpha level is chosen to set limits of acceptable probability for the role of chance in the observed distinctions. The level of alpha is used either for direct comparison with a single P-value, or for determining the extent of a confidence interval. "Statistical significance" is proclaimed if the calculations yield a P-value that is below alpha, or a 1-alpha confidence interval whose range excludes the null result of "no difference." Both the P-value and confidence-interval methods are essentially reciprocal, since they use the same principles of probabilistic calculation; and both can yield distorted or misleading results if the data do not adequately conform to the underlying mathematical requirements. The major scientific disadvantage of both methods is that their "significance" is merely an inference derived from principles of mathematical probability, not an evaluation of substantive importance for the "big" or "small" magnitude of the observed distinction. The latter evaluation has not received adequate attention during the emphasis on probabilistic decisions; and careful principles have not been developed either for the substantive reasoning or for setting appropriate boundaries for "big" or "small." After a century of "significance" inferred exclusively from probabilities, a basic scientific challenge is to develop methods for deciding what is substantively impressive or trivial.

Confidence Intervals↗

Genetic counseling in rare syndromes: a resampling method for determining an approximate confidence interval for gene location with linkage data from a single pedigree.

Multipoint linkage analysis is a powerful method for mapping a rare disease gene on the human gene map despite limited genotype and pedigree data. However, there is no standard procedure for determining a confidence interval for gene location by using multipoint linkage analysis. A genetic counselor needs to know the confidence interval for gene location in order to determine the uncertainty of risk estimates provided to a consultant on the basis of DNA studies. We describe a resampling, or "bootstrap," method for deriving an approximate confidence interval for gene location on the basis of data from a single pedigree. This method was used to define an approximate confidence interval for the location of a gene causing nonsyndromal X-linked mental retardation in a single pedigree. The approach seemed robust in that similar confidence intervals were derived by using different resampling protocols. Quantitative bounds for the confidence interval were dependent on the genetic map chosen. Once an approximate confidence interval for gene location was determined for this pedigree, it was possible to use multipoint risk analysis to estimate risk intervals for women of unknown carrier status. Despite the limited genotype data, the combination of the resampling method and multipoint risk analysis had a dramatic impact on the genetic advice available to consultants.

Chromosome Mapping↗

Effective sample sizes for confidence intervals for survival probabilities.

We examine various methods to estimate the effective sample size for construction of confidence intervals for survival probabilities. We compare the effective sample sizes of Cutler and Ederer and Peto et al., as well as a modified Cutler-Ederer effective sample size. We investigate the use of these effective sample sizes in the common situation of many censored observations that intervene between the time point of interest and the last death before this time. We note that there is no a priori reason to treat upper and lower confidence intervals in a symmetric fashion since censored survival data are by nature asymmetric. We recommend the use of the Cutler-Ederer effective sample size in construction of upper confidence intervals and the Peto effective sample size in construction of lower confidence intervals. Two examples with real data demonstrate the differences between confidence intervals formed with different effective sample sizes. This study also illustrates the need for caution in the application of simulation studies to real problems.

Bacterial Infections↗

Confidence intervals for postcensal state population estimates.

This paper develops a methodology for constructing confidence intervals around postcensal state population estimates. Using regression equations, forecast intervals are derived around the average age-specific death rates over the postcensal estimation period. These results, combined with the number of postcensal deaths and the most current census counts, are translated into confidence intervals for the age structure. Two approaches are offered for constructing total population confidence intervals. One examines a simulated distribution while the other focuses on the mathematical derivation of population means and variances. The methodology is illustrated by deriving statistically defensible confidence intervals around the July 1, 1975 population of Florida.

Adolescent↗

Population forecasts and confidence intervals for Sweden: a comparison of model-based and empirical approaches.

This paper compares several methods of generating confidence intervals for forecasts of population size. Two rest on a demographic model for age-structured populations with stochastic fluctuations in vital rates. Two rest on empirical analyses of past forecasts of population sizes of Sweden at five-year intervals from 1780 to 1980 inclusive. Confidence intervals produced by the different methods vary substantially. The relative sizes differ in the various historical periods. The narrowest intervals offer a lower bound on uncertainty about the future. Procedures for estimating a range of confidence intervals are tentatively recommended. A major lesson is that finitely many observations of the past and incomplete theoretical understanding of the present and future can justify at best a range of confidence intervals for population projections. Uncertainty attaches not only to the point forecasts of future population, but also to the estimates of those forecasts' uncertainty.

Forecasting↗

Confidence intervals for a variance ratio, or for heritability, in an unbalanced mixed linear model.

A procedure is presented for constructing an exact confidence interval for the ratio of the two variance components in a possibly unbalanced mixed linear model that contains a single set of m random effects. This procedure can be used in animal and plant breeding problems to obtain an exact confidence interval for a heritability. The confidence interval can be defined in terms of the output of a least squares analysis. It can be computed by a graphical or iterative technique requiring the diagonalization of an m X m matrix or, alternatively, the inversion of a number of m X m matrices. Confidence intervals that are approximate can be obtained with much less computational burden, using either of two approaches. The various confidence interval procedures can be extended to some problems in which the mixed linear model contains more than one set of random effects. Corresponding to each interval procedure is a significance test and one or more estimators.

Analysis of Variance↗

On sample-size and power calculations for studies using confidence intervals.

A recent trend in epidemiologic analysis has been away from significance tests and toward confidence intervals. In accord with this trend, several authors have proposed the use of expected confidence intervals in the design of epidemiologic studies. This paper discusses how expected confidence intervals, if not properly centered, can be misleading indicators of the discriminatory power of a study. To rectify such problems, the study must be designed so that the confidence interval has a high probability of not containing at least one plausible but incorrect parameter value. To achieve this end, conventional formulas for power and sample size may be used. Expected intervals, if properly centered, can be used to design uniformly powerful studies but will yield sample-size requirements far in excess of previously proposed methods.

Epidemiologic Methods↗

Confidence interval construction for proportion difference in small-sample paired studies.

Paired dichotomous data may arise in clinical trials such as pre-/post-test comparison studies and equivalence trials. Reporting parameter estimates (e.g. odds ratio, rate difference and rate ratio) along with their associated confidence interval estimates becomes a necessity in many medical journals. Various asymptotic confidence interval estimators have long been developed for differences in correlated binary proportions. Nevertheless, the performance of these asymptotic methods may have poor coverage properties in small samples. In this article, we investigate several alternative confidence interval estimators for the difference between binomial proportions based on small-sample paired data. Specifically, we consider exact and approximate unconditional confidence intervals for rate difference via inverting a score test. The exact unconditional confidence interval guarantees the coverage probability, and it is recommended if strict control of coverage probability is required. However, the exact method tends to be overly conservative and computationally demanding. Our empirical results show that the approximate unconditional score confidence interval estimators based on inverting the score test demonstrate reasonably good coverage properties even in small-sample designs, and yet they are relatively easy to implement computationally. We illustrate the methods using real examples from a pain management study and a cancer study.

Biometry↗

Estimating confidence intervals for cost-effectiveness ratios: an example from a randomized trial.

Cost-effectiveness ratios usually appear as point estimates without confidence intervals, since the numerator and denominator are both stochastic and one cannot estimate the variance of the estimator exactly. The recent literature, however, stresses the importance of presenting confidence intervals for cost-effectiveness ratios in the analysis of health care programmes. This paper compares the use of several methods to obtain confidence intervals for the cost-effectiveness of a randomized intervention to increase the use of Medicaid's Early and Periodic Screening, Diagnosis and Treatment (EPSDT) programme. Comparisons of the intervals show that methods that account for skewness in the distribution of the ratio estimator may be substantially preferable in practice to methods that assume the cost-effectiveness ratio estimator is normally distributed. We show that non-parametric bootstrap methods that are mathematically less complex but computationally more rigorous result in confidence intervals that are similar to the intervals from a parametric method that adjusts for skewness in the distribution of the ratio. The analyses also show that the modest sample sizes needed to detect statistically significant effects in a randomized trial may result in confidence intervals for estimates of cost-effectiveness that are much wider than the boundaries obtained from deterministic sensitivity analyses.

Analysis of Variance↗

Comparison of family-based association tests in chromosome regions selected by linkage-based confidence intervals.

We use the Genetic Analysis Workshop 14 simulated data to explore the effectiveness of a two-stage strategy for mapping complex disease loci consisting of an initial genome scan with confidence interval construction for gene location, followed by fine mapping with family-based tests of association on a dense set of single-nucleotide polymorphisms. We considered four types of intervals: the 1-LOD interval, a basic percentile bootstrap confidence interval based on the position of the maximum Zlr score, and asymptotic and bootstrap confidence intervals based on a generalized estimating equations method. For fine mapping we considered two family-based tests of association: a test based on a likelihood ratio statistic and a transmission-disequilibrium-type test implemented in the software FBAT. In two of the simulation replicates, we found that the bootstrap confidence intervals based on the peak Zlr and the 1-LOD support interval always contained the true disease loci and that the likelihood ratio test provided further strong confirmatory evidence of the presence of disease loci in these regions.

Chromosomes, Human↗

A score method of constructing asymmetric confidence intervals for the mean of a rating scale item.

This article presents a generalization of the Score method of constructing confidence intervals for the population proportion (E. B. Wilson, 1927) to the case of the population mean of a rating scale item. A simulation study was conducted to assess the properties of the Score confidence interval in relation to the traditional Wald (A. Wald, 1943) confidence interval under a variety of conditions, including sample size, number of response options, extremeness of the population mean, and kurtosis of the response distribution. The results of the simulation study indicated that the Score interval usually outperformed the Wald interval, suggesting that the Score interval is a viable method of constructing confidence intervals for the population mean of a rating scale item.

Confidence Intervals↗

Use of confidence intervals and sample size calculations in health economic studies.

OBJECTIVE: To discuss the calculation and application of confidence intervals in pharmacoeconomic studies. DATA SYNTHESIS: The increasing frequency with which pharmacoeconomic evaluations are made within clinical trials makes it possible to obtain information on the outputs and costs of an intervention in each patient of a sample under study. This allows the same statistical principles commonly used in clinical trials to be applied to cost or cost-effectiveness data. The methodology described in this article would allow expression of cost-effectiveness ratios in the form of confidence intervals. The calculation of the cost-effectiveness ratio by means of a confidence interval may have important practical consequences, both in decision-making on the choice of 1 intervention versus another and in calculating the size of the sample necessary to identify statistically significant differences, from both clinical and economic points of view. CONCLUSIONS: The complementary use of confidence intervals and sensitivity analysis makes it possible to measure uncertainty related and unrelated to variability in sample data, allowing the decision to adopt 1 technology or another to be based on the most objective information available. Although several ethical and methodologic concerns remain to be addressed, this methodology may contribute to improving the more rational and efficient use of drugs.

Confidence Intervals↗

Bronchodilator testing "confidence intervals" based on the level of bronchial responsiveness.

"Confidence intervals" based upon inhalation of placebo have been proposed as criteria for defining a significant response to an inhaled bronchodilator. The published intervals were derived from a clinically heterogeneous population. We calculated the difference (delta) between spirometric data before and after placebo in 109 consecutive patients referred for methacholine bronchoprovocation challenge testing. The mean delta, expressed both as a percent change and as actual volume change for both the FVC and FEV1, was not significantly different in patients with bronchial hyperresponsiveness, as compared to subjects with a negative methacholine challenge test; however, the variance of measurements in hyperresponsive subjects was significantly greater than that of the normal population. In addition, as the category of responsiveness increased from mild to moderate to severe hyperresponsiveness, so did the variance within these groups. A negative correlation between the measured PC20FEV1 and the volume and percent change was noted. We conclude that patients with hyperresponsive airways may display increased spirometric variation before and after placebo. This general approach for establishing normal limits for defining a significant response appears to be valid, but the actual values used may vary, depending on the composition of the population tested and the goals of the study. Also, the use of the term, "confidence intervals," in this context is inappropriate; and we propose, instead, the use of percentiles and the simpler terms, upper 90th or 95th percentiles.

Adult↗

The case for confidence intervals in controlled clinical trials.

A statistical wit once remarked that researchers often pose the wrong question and then proceed to answer that question incorrectly. The question that researchers intend to ask is whether or not a treatment effect is clinically significant. The question that is typically asked, however, is whether or not the treatment effect is statistically significant--a question that may be only marginally related to the issue of clinical impact. Similarly, the response, in the form of a p value, is typically assumed to reflect clinical significance but in fact reflects statistical significance. In an attempt to address this problem the medical literature over the past decade has been moving away from tests of significance and toward the use of confidence intervals. Concretely, study reports are moving away from "the difference was significant with a p value under 0.01" and toward "the one-year survival rate was increased by 20 percentage points with a 95% confidence interval of 15 to 24 percentage points." By focusing on what the effect is rather than on what the effect is not confidence intervals offer an appropriate framework for reporting the results of clinical trials. This paper offers a non-technical introduction to confidence intervals, shows how the confidence intervals framework offers advantages over hypothesis testing, and highlights some of the controversy that has developed around the application of this method. Additionally, we make the argument that studies which will be reported in terms of confidence intervals should similarly be planned with reference to confidence intervals. The sample size should be set to ensure that the estimates of effect size will be reported not only with adequate power but also with appropriate precision.

Confidence Intervals↗

Simultaneous confidence intervals for ratios with applications to the comparison of several treatments with a control.

OBJECTIVES: In this article, we illustrate and compare exact simultaneous confidence sets with various approximate simultaneous confidence intervals for multiple ratios as applied to many-to-one comparisons. Quite different datasets are analyzed to clarify the points. METHODS: The methods are based on existing probability inequalities (e.g., Bonferroni, Slepian and Sidak), estimation of nuisance parameters and re-sampling techniques. Exact simultaneous confidence sets based on the multivariate t-distribution are constructed and compared with approximate simultaneous confidence intervals. RESULTS: It is found that the coverage probabilities associated with the various methods of constructing simultaneous confidence intervals (for ratios) in manyto-one comparisons depend on the ratios of the coefficient of variation for the mean of the control group to the coefficient of variation for the mean of the treatments. If the ratios of the coefficients of variations are less than one, the Bonferroni corrected Fieller confidence intervals have almost the same coverage probability as the exact simultaneous confidence sets. Otherwise, the use of Bonferroni intervals leads to conservative results. CONCLUSIONS: When the ratio of the coefficient of variation for the mean of the control group to the coefficient of variation for the mean of the treatments are greater than one (e.g., in balanced designs with increasing effects), the Bonferroni simultaneous confidence intervals are too conservative. Therefore, we recommend not using Bonferroni for this kind of data. On the other hand, the plug-in method maintains the intended confidence coefficient quite satisfactorily; therefore, it can serve as the best alternative in any case.

Abdominal Pain↗

Uncertainty of incremental cost-effectiveness ratios. A comparison of Fieller and bootstrap confidence intervals.

OBJECTIVE: To compare different methods to estimate the confidence interval of the incremental cost-effectiveness ratio (ICER). METHODS: The adequacy of Fieller intervals and three methods for calculating bootstrap intervals are compared based on a simulation of 10,000 trials, using data from one trial. RESULTS: Both Fieller and bootstrap methods lead to unsatisfactory results when the difference in effectiveness is approximately zero. Where this difference is significant, the four methods for calculating confidence intervals for ICER do not give very different results, but Fieller's interval performs best. CONCLUSIONS: Since Fieller's confidence limits are relatively easy to compute compared with bootstrap simulations, we recommend using this method.

Child↗

Comparison of three methods of estimating confidence intervals for stereotactic error.

When planning a stereotactic procedure, it is clinically valuable to know the spatial confidence intervals of a particular stereotactic technique. To do this, the aggregate error distribution of the stereotactic technique must first be estimated. In a frame-based stereotactic procedure, there is an imaging step and a treatment delivery step. If error is introduced independently at these steps, then the error of a stereotactic procedure may be computed from the error distributions of the component steps. Three computational methods of doing this were compared: parametric, convolution, and Monte Carlo. To test these methods, the error distributions of an imaging technique, a delivery technique, and the corresponding stereotactic imaging-plus-delivery system were measured empirically using a phantom, computed tomography, and the CRW stereotactic system. The three methods gave concordant estimates of mean aggregate error (respectively 2.71 +/- 1.52, 2.45 +/- 2.30, 2.51 +/- 2.34, and 2.47 +/- 2.31 mm for the empiric, convolution, Monte Carlo, and parametric methods). However, the estimates of the confidence intervals differed between the parametric and the nonparametric methods. In particular, the parametric method gave significantly higher estimates of the 99% spatial confidence interval (6.40 mm versus 5.41 mm and 5.38 mm for the convolution and Monte Carlo methods). Knowledge of the confidence intervals allows a neurosurgeon to determine a priori whether a particular stereotactic technique is likely to satisfy a clinically defined error budget, and thereby achieve clinical success.

Confidence Intervals↗

A simple method to calculate resolving power and confidence interval of QTL map location.

"Resolving power" is defined as the 95% confidence interval for quantitative trait locus (QTL) map location that would be obtained when scoring an infinite number of markers in a given constellation of a marker-QTL mapping experiment. Resolving power can serve as a close estimate of the confidence interval of QTL map location, as well as a guide to the lower efficient limit of marker spacing in an initial marker-QTL mapping experiment. In the present study, an extensive series of simulations was carried out to provide estimates of resolving power, for backcross (BC) and F2 designs, over a wide range of experimental sizes and of gene effects and dominance at the QTL. From the simulation results, the remarkably simple expressions, 3000/(mNd2) (where m = 1 for BC and m = 2 for F2; N = population size, and d = allele substitution effect) and 530/Nv (in terms of v, the proportion of variance explained), were obtained for estimating resolving power. These expressions can provide a convenient guide to planning marker spacing in BC and F2 marker-QTL linkage experiments and for placing confidence intervals about QTL map location obtained in such experiments.

Animals↗