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Studying new antidepressants: if there were a light at the end of the tunnel, could we see it?

This commentary began with the proposition that the SSRIs have become the standard of comparison for new antidepressants. It is also suggested that the conventional wisdom that all antidepressants are equally effective is no longer true. Rather, it is asserted that the same factors that have compromised the sensitivity of RCTs to detect drug-placebo differences similarly have impaired discriminations between effective and even more effective antidepressants. In order to have the power to make such a distinction, an RCT may need to enroll 300 or more patients per cell. Few studies thus have adequate statistical power. Alternatively, conclusions can be drawn from quantitative methods that combine data from groups of smaller studies. The relative merits and limitations of 2 strategies used to examine the results of comparative studies, meta-analysis and pooled analysis, were discussed. The former method is preferred when there are a large number of relevant RCTs; however, failure to include unpublished data from all relevant studies may inflate results. The latter method, unless biased by selective inclusion of studies or marked heterogeneity of results, is preferred when there are only a handful of comparable studies. Although the task of selecting among a number of good choices remains more clinical art than science, quantitative methods are now available to help determine if there are clinically meaningful differences in antidepressant efficacy. The conventional RCT provides a low power telescope for visualizing differences between effective medications. If there were a light at the end of the tunnel, it would be difficult to see it. Until methods that can improve the ability to discriminate between an active antidepressant and a placebo are identified and implemented, the ability to see modest differences necessitates the use of statistical methods such as meta-analysis and pooled analysis of original data.

Antidepressive Agents↗

Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya.

It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeat-pseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-effects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 micrograms ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/ day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm-3, and numbers of parasites mm-3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P = 0.514, efficacy 9%, statistical power 95% probability of efficacy < 50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania.

Animals↗

A Bayesian statistical analysis of human T-cell lymphotropic virus evolutionary rates.

HTLV is a genetically-stable retrovirus that is considered to have evolved partly in concert with human migrations. Its rate of evolution is low and therefore, difficult to estimate reliably. In the first part of this study, we provide an improved estimate of HTLV evolutionary rate using anthropological calibration of phylogenetic nodes. We investigate two different anthropological calibrations using a Bayesian method that implements a relaxed molecular clock model and can combine data from multiple genes. The analysis shows that the two calibrations are compatible. In the second part, we develop a Bayesian statistical model to combine and compare the anthropology-based estimates of evolutionary rate with a rate recently calculated using pedigree data from vertically HTLV-infected families. We compare the statistical power of the two estimates and show that the current pedigree estimate, although resulting in considerably higher evolutionary rates, is too statistically weak to warrant a re-examination of the commonly used anthropology-based estimates. Statistical uncertainty burdens HTLV rate estimates based on both anthropological calibrations and on pedigree data; the former method rests on an untested assumption, whilst that latter is affected by small sample sizes.

Bayes Theorem↗

Comparison of hospital costing methods in an economic evaluation of a multinational clinical trial.

OBJECTIVES: To develop and evaluate strategies for estimating hospitalization costs in multinational clinical trials. METHODS: Hospital cost estimates for eleven diagnoses were collected from twelve countries participating in a trial of therapies for congestive heart failure. Estimates were combined with U.S.-based diagnosis-related group weights to compute country-specific unit cost estimates for all reasons for hospitalization. Variations of hospital costing methods were developed. The unit cost method assigns a country-specific unit cost estimate to each hospitalization. The other methods adjust for length of stay using a daily cost (DC) estimate for each diagnosis, based on either the mean length of stay (DC-mean method) or the median length of stay (DC-median method) for each diagnosis in each country. Additional modifications were explored through adjustment of the distribution of daily costs incurred during a hospital stay. RESULTS: The mean cost for all hospitalizations was dollars 10,242 (SD, 10,042) using the unit cost method, dollars 10,242 (SD, 12,760) using the standard DC-mean method, and dollars 13,967 (SD, 18,762) using the standard DC-median method. In comparisons of costs for all 5,486 hospitalizations incurred by a subset of 2,352 patients in the trial, the unit cost method provided 92% power to detect a dollars 1,000 cost difference. The standard DC-mean method provided 76% power, and the standard DC-median method provided 44% power. CONCLUSIONS: Hospital costing methods that adjust for differences in length of stay require a significantly larger sample to attain comparable statistical power as methods that assign unadjusted unit cost estimates to hospitalization events.

Clinical Trials as Topic↗

Reproducibility of time at or near VO2max during intermittent treadmill running.

The purpose of this study was to determine the reproducibility of time at or above 90 % (t (90 % )VO (2max)) and 95 % (t (95 % )VO (2max)) maximal oxygen uptake during an intermittent treadmill run to exhaustion. Twenty-two distance runners (age 38.0 +/- 7.1 yrs) performed two identical incremental and two identical intermittent tests on four separate days. Respiratory exchange was measured continuously throughout each test by an automated open-circuit gas analysis system. The incremental test consisted of increases in treadmill speed every minute until volitional exhaustion. The highest averaged 30-s oxygen uptake (VO (2)) value was defined as VO (2max) and the minimum speed that elicited VO (2max) was defined as vVO (2max). The intermittent test consisted of 30-s work intervals ran at 105 % vVO (2max) interspersed by 30-s relief intervals ran at 60 % vVO (2max) and was continued until volitional exhaustion. The time that VO (2) was at or above 90 % and 95 % of the mean maximum values elicited during the two previous incremental tests was determined for the intermittent tests. The mean t (95 % )VO (2max) was 232 (SD 174) s and 244 (SD 195) s and the mean t (90 % )VO (2max) was 480 (SD 220) s and 488 (SD 252) s, for trial 1 and trial 2, respectively. Reproducibility statistics for t (95 % )VO (2max) and t (90 % )VO (2max), respectively, were: 95 % limits of agreement 12 +/- 227 s and 8 +/- 328 s; coefficient of variation 34.5 % and 24.5 %; and intraclass correlation coefficient 0.80 and 0.75. Statistical power analysis indicated that this level of reproducibility would allow mean differences of 15 - 20 % between intermittent training protocols to attain statistical significance in future experimental research, with sample sizes probably within the resources of most researchers.

Adult↗

Maintaining data integrity in randomized clinical trials.

BACKGROUND: The process of attaining and maintaining data integrity is critical to ensure a successful randomized clinical trial. Methodologic strategies to achieve data integrity when repeated measures are used has not been discussed in detail in the literature. The National Institutes of Health requires that data integrity and safety monitoring boards or plans be established for randomized clinical trials. OBJECTIVES: The objectives of this paper are to (a) examine important data collection issues nurse scientists often encounter in randomized clinical trials and (b) present a process that researchers can apply to achieve data integrity. METHODS: The process to achieve data integrity is based on strategies that were developed by an interdisciplinary hospice research team involved in an ongoing National Institutes of Health-funded clinical trial. The process and key issues are illustrated with methodologic examples from the randomized clinical trial and supporting literature. RESULTS: The process of achieving data integrity involves developing protocols in three key areas: data collection, training of data collectors, and data monitoring. The use of these protocols will increase the rigor of the clinical trial and assist in maintaining study validity. CONCLUSIONS: Investigators conducting clinical trials need to consider all issues involved in achieving data integrity and have tested protocols in place throughout the study. These approaches will not only help maintain study validity but also help ensure data of sufficient quantity and quality to achieve the desired statistical power.

Bias↗

Power considerations in epidemiologic studies of vinyl chloride workers.

Nine retrospective mortality studies of workers exposed to vinyl chloride were reviewed to determine whether differences in their hypothesis testing results might be due to differences in statistical power. Where possible, the power of each study was calculated for cancer of the lung, brain and liver. When power was taken into consideration, the results for liver and brain cancer were found to be consistent with an etiologic role for vinyl chloride. For lung cancer, the data were not consistent with an etiologic role in that two studies with very high power yielded negative results.

Brain Neoplasms↗

Power of 'phase 0' chronobiologic trials at different signal-to-noise ratios and sample sizes.

Clinical trials would gain from incorporating 'Phase 0' chronobiologic pilot designs both from the viewpoint of (statistical) power and cost-effectiveness. Herein, this statement is documented by power computations and is further illustrated by clinical examples answering specific questions. Power computations show the merits both of chronobiologic designs (that assign samples at equidistant intervals to cover one full cycle of anticipated pertinent rhythms) and of chronobiologic analyses (the cosinor versus the analysis of variance). Randomized clinical trials would gain from incorporating a concern for timing as well as dosing in all three stages of clinical trials (Phase I, II and III focusing on toxicity, efficacy and a comparison with the current best treatment, respectively) and could be cost-effectively preceded by 'Phase 0' trials so as to detect, sooner and with smaller sample sizes, desired or undesired effects that may otherwise be missed.

Analysis of Variance↗

Increasing the degrees of freedom in future group randomized trials: the df* approach.

This article builds on the previous article by Blitstein et al. (2005), which showed how external estimates of intraclass correlation can be used to improve the precision for the analysis of an existing group randomized trial. The authors extend that work to sample size estimation and power analysis for future group-randomized trials. Often this approach will allow a smaller study than would otherwise be possible without sacrificing statistical power. Such studies are needed, for example, as pilot studies to help plan for a full-scale efficacy trial, as replication studies, or in situations in which resource constraints prohibit a larger trial. The authors discuss the circumstances under which this strategy will be most helpful and the risks associated with conducting smaller studies.

Humans↗

Mapping structural differences of the corpus callosum in individuals with 18q deletions using targetless regional spatial normalization.

Individuals with a constitutional chromosome abnormality consisting of a deletion of a portion of the long arm of chromosome 18 (18q-) have a high incidence ( approximately 95%) of dysmyelination. Neuroradiologic findings in affected children report a smaller corpus callosum, but this finding has not been quantified. This is in part due to the large intersubject variability of the corpus callosum size and shape and the small number of subjects with 18q-, which leads to low statistical power for comparison with typically developing children. An analysis method called targetless spatial normalization (TSN) was used to improve the sensitivity of statistical testing. TSN converges all images in a group into what is referred as group common space. The group common space conserves common shape, size, and orientation while reducing intragroup variability. TSN in conjunction with a Witelson vertical partitioning scheme was used to assess differences in corpus callosum size between 12 children with 18q- and 12 age-matched normal controls. Significant global and regional differences in corpus callosum size were seen. The 18q- group showed an overall smaller (25%) corpus callosum (P < 10(-7)), even after correction for differences in brain size. Regionally, the posterior portions of corpus callosum (posterior midbody, isthmus, and splenium), which contain heavily myelinated fibers, were found to be 25% smaller in the population with 18q-.

Agenesis of Corpus Callosum↗

Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis.

The set of LXS recombinant inbred (RI) strains is a new and exceptionally large mapping panel that is suitable for the analysis of complex traits with comparatively high power. This panel consists of 77 strains-more than twice the size of other RI sets--and will typically provide sufficient statistical power (beta = 0.8) to map quantitative trait loci (QTLs) that account for approximately 25% of genetic variance with a genomewide p < 0.05. To characterize the genetic architecture of this new set of RI strains, we genotyped 330 MIT microsatellite markers distributed on all autosomes and the X Chromosome and assembled error-checked meiotic recombination maps that have an average F2-adjusted marker spacing of approximately 4 cM. The LXS panel has a genetic structure consistent with random segregation and subsequent fixation of alleles, the expected 3-4 x map expansion, a low level of nonsyntenic association among loci, and complete independence among all 77 strains. Although the parental inbred strains-Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS)--were derived originally by selection from an 8-way heterogeneous stock selected for differential sensitivity to sedative effects of ethanol, the LXS panel is also segregating for many other traits. Thus, the LXS panel provides a powerful new resource for mapping complex traits across many systems and disciplines and should prove to be of great utility in modeling the genetics of complex diseases in human populations.

Alleles↗

Conditions, interventions, and outcomes in nursing research: a comparative analysis of North American and European/International journals. (1981-1990).

This study compared the conceptual foci and methodological characteristics of research projects which tested the effects of nursing interventions, published in four general nursing research journals with predominantly North American, and two with predominantly European/International authorship and readership. Dimensions and variables of comparison included: nature of subjects, design issues, statistical methodology, statistical power, and types of interventions and outcomes. Although some differences emerged, the most striking and consistent finding was that there were no statistically significant differences (and thus similarities) in the content foci and methodological parameters of the intervention studies published in both groups of journals. We conclude that European/International and North American nursing intervention studies, as reported in major general nursing research journals, are highly similar in the parameters studied, yet in need of overall improvement. Certainly, there is no empirical support for the common (explicit or implicit) ethnocentric American bias that leadership in nursing intervention research resides with and in the United States of America.

Adult↗

Body mass index is the main risk factor for arterial hypertension in young subjects without major comorbidity.

BACKGROUND: Analytical statistics revealed a variety of risk factors for hypertension, but the complex interplay between different factors remains to be determined by more powerful statistical techniques. METHODS: Analytical as well as new, explorative statistical methods such as natural segmentation (k-means) and predictive modelling algorithms (C4.5) were used to classify the interactions of the individual risk factors for arterial hypertension in a large cohort of subjects. Fifty-five attributes (subject base, sociodemographic, medical history, laboratory data) were obtained from each of the 3547 participants of a community-based health survey. The study subjects, mean age of 41 years, were free of major comorbidity. RESULTS: Twenty-five percent of the subjects had at least stage 1 hypertension. No clear linear dependency of risk factors with the diagnosis hypertension could be derived by the analytical statistics. In particular, the mutual amplification of different risk factors towards hypertension could not be revealed by these techniques. Explorative analytics however, uncovered body mass index (BMI) as the main single risk factor associated with hypertension. High predictive accuracy was achieved when combinations of certain risk factors including male gender and age were used. CONCLUSIONS: In summary, the survey of risk factors for hypertension using explorative analytics yielded high increases for the correct prediction of arterial hypertension. In this cohort, BMI was the single strongest parameter associated with arterial hypertension.

Adult↗

Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Adenocarcinoma↗

Comparing automatic and manual image processing in FLARE assay analysis for colon carcinogenesis.

Measurement of the amount of oxidative damage to DNA is one tool that can be used to estimate the beneficial effect of diet on the prevention of colon carcinogenesis. The FLARE assay is a modification of the single-cell gel electrophoresis (Comet) assay, and provides a measure of the 8OHdG adduct in the cells. In this paper, we present two innovations to the existing methods of analysis. The first one is related to the FLARE assay itself. We describe automated image analysis techniques that can be expected to measure oxidative damage faster, reproducibly, with less noise, and hence achieve greater statistical power. The proposed technique is compared to an existing technique, which was more manual and thus slower. The second innovation is our statistical analysis: we exploit the shape of FLARE intensity histograms, and show statistically significant diet effects in the duodenum. Previous analyses of this data concentrated on simple summary statistics, and found only marginally statistically significant diet effects. With the new imaging method and measure of oxidative damage, we show cells in the duodenum exposed to fish oil as having more oxidative damage than cells exposed to corn oil.

Journal Article↗

Identifying subgroups of the general population that may be susceptible to short-term increases in particulate air pollution: a time-series study in Montreal, Quebec.

This study was undertaken in order to shed light on which groups of the general population may be susceptible to the effects of ambient particles. The objectives of the study were (1) to determine whether concentrations of particles in the ambient air of Montreal, Quebec, were associated with daily all-cause and cause-specific mortality in the period 1984 to 1993, and (2) to determine whether groups of the population had higher than average risks of death from exposure to particles. From the network of fixed-site air pollution monitors in Montreal we obtained daily mean levels of various measures of particles, gaseous pollutants, and weather variables measured at Dorval International Airport. We also used measurements of sulfate from an acid rain monitoring station 150 km southeast of the city (Sutton, Quebec). We estimated associations for particulate matter (PM) with an aerodynamic diameter of 10 microns or smaller (PM10), or 2.5 microns or smaller (PM2.5), total suspended particles (TSP), coefficient of haze (COH), an extinction coefficient, and sulfate. Because substantial data for fine particles were missing, we developed a regression model to predict PM2.5 and to predict sulfate from PM2.5. In the main body of the report, we present results for COH, predicted PM2.5, and sulfate. Detailed results for all pollutants are included in Appendices H through O, which are available on request from Health Effects Institute and from the HEI web site at www.healtheffects.org. To address the first objective, we made use of the underlying causes of death among all 140,939 residents of Montreal who died between 1984 and 1993. We regressed the logarithm of daily counts of cause-specific mortality on the daily mean levels for a variety of measures of particles, accounting for seasonal and subseasonal fluctuations in the mortality time series, overdispersion, and weather factors. To address the second objective, we developed algorithms to define conditions that subjects had prior to death, with the focus on cardiopulmonary diseases. These algorithms were based on information retained on the databases of the universal Quebec Health Insurance Plan (QHIP). The databases include records of all procedures (e.g., type of surgery), physician visits, and consultations carried out by all physicians in Quebec. For persons > or = 65 years and for all recipients of social assistance the prescription database contains records of all pharmaceuticals dispensed (type of medication, dose, quantity). For each group of conditions defined, we used the same statistical model that was used in the analyses of all nonaccidental causes of death. In the analyses of cause-specific mortality, we found evidence of associations for all nonaccidental causes of death and specific causes of death--cancer, coronary artery disease, respiratory diseases, and diabetes--that were consistent across most metrics of ambient air particle concentrations, evaluated as the 3-day mean of particle concentrations measured on the day of death (lag 0) and on each of the two days before death (lag 1, lag 2). Associations for all cardiovascular diseases combined were found only with sulfate. As well, we generally found increased daily mortality for persons 65 years of age and over. The results for all nonaccidental causes of death are similar to findings from other studies; the mean percent increase in mortality for a 100 micrograms/m3 increase in daily TSP at lag 0 was 6.7%. In the analyses of the groups defined from the QHIP data, there was little evidence of associations with air pollutants among persons who before death were classified as having acute or chronic upper respiratory diseases, airways diseases, hypertension, acute coronary artery diseases, and cerebrovascular diseases. On the other hand, we found consistent increases across most types of ambient particles for persons who had cancer, acute lower respiratory diseases, any form of cardiovascular disease, chronic coronary artery diseases, and congestive heart failure. As well, we found an association for individuals who did not have any cardiovascular disease, lower respiratory diseases, and cancer. This latter group consisted of persons who had no interactions with the health care system one year before death (12%) and individuals with a wide variety of potentially fatal diseases (52%), including neurological conditions (12%), diabetes (8%), cardiac dysrhythmias (8%), dementia (6%), organic psychotic disorders (6%), and anemias (4%). As statistical power was reduced in the analyses presented above, differences between groups (e.g., < 65 and > or = 65 year age groups) were not usually statistically significant. The association with diabetes has not been reported previously, and this needs to be replicated in other studies. (ABSTRACT TRUNCATED)

Age Factors↗

[Near triad meter--dynamic measurement of pupillometry with horizontal eye tracker by accommodative stimulation].

PURPOSE: A newly developed "Near Triad Meter" is a useful tool to record the dynamics of pupils and horizontal eye movements in both eyes simultaneously with the accommodative stimuli. The responses show insufficiency or strain for accommodation. In this study the objective accommodative power (in diopters, D) is calculated by the measurement of pupillary constriction-ratio(CR) and compared in 4 age groups to find the age-related decrement of diopter values. METHOD: A clearly visible accommodative target was moved back-and-forth from 50 cm to [near point + 1 D] (maximum accommodative stimulus; MAS). The speed was regulated constant for diopter movement. Pupillometry and eye tracker were recorded simultaneously with MAS in both eyes together. Three trials were done on 42 volunteers in each age group from 20-year-olds to 50-year-olds and the most reliable recording was used to measure the CR. Eighteen well-responding volunteers were selected to make the standard curves of CR by step-by-step accommodative stimuli. The mean CRs of initial tests with MAS were applied to the age-matched standard curves to calculate the maximum accommodative diopter value. RESULTS: The mean CRs versus MAS in each age group were 48%/7.2 D in the 20-year group, 46%/6.9 D in the 30-year group, 35%/3.6 D in the 40-year group, and 33%/3.1 D in the 50-year group. The mean values of CR were applied to age-matched standard curves to obtain the maximum accommodative power, which was 8.0 D in the 20-year group, 9.1 D in the 30-year group, 3.4 D in the 40-year group, and 4.1 D in the 50-year group. The 20- and 30-year olds showed equal power statistically, The remarkable age-dependent difference was calculated quantitatively. CONCLUSION: The dynamics of near response revealed the individual summation of accommodative power including depth of focus, and accommodative vergence objectively and quantitatively. This method is useful for understanding the quality of accommodative insufficiency and also the quantity of accommodative width, including presbyopia.

Accommodation, Ocular↗

Developing a prognostic model in the presence of missing data: an ovarian cancer case study.

When developing prognostic models in medicine, covariate data are often missing and the standard response is to exclude those individuals whose data are incomplete from the analyses. This practice leads to a reduction in the statistical power, and may lead to biased results. We wished to develop a prognostic model for overall survival from 1,189 primary cases (842 deaths) of epithelial ovarian cancer. A complete case analysis restricted the sample size to 518 (380 deaths). After applying a multiple imputation (MI) framework we included three real values for each one imputed, and constructed a model composed of more statistically significant prognostic factors and with increased predictive ability. Missing values can be imputed in cases where the reason for the data being missing is known, particularly where it can be explained by available data. This will increase the power of an analysis and may produce models that are more statistically reliable and applicable within clinical practice.

Adolescent↗