Intricate decision making: ambivalences and barriers when fulfilling an advance directive.

BACKGROUND: Despite a recent statutory ruling stating the binding nature of advance directives (ADs), only a minority of the population has signed one. Yet, a majority deem it of utmost importance to ensure their wishes are followed through in case they are no longer able to decide. The reasons for this discrepancy have not yet been investigated sufficiently. PATIENTS AND METHODS: This article is based on a survey of patients using a well-established structured questionnaire. First, patients were asked about their attitudes with respect to six therapeutic options at the end of life: intravenous fluids, artificial feeding, antibiotics, analgesia, chemotherapy/dialysis, and artificial ventilation; and second, they were asked about the negative effects related to the idea of ADs surveying their apprehensions: coercion to fulfill an AD, dictatorial reading of what had been laid down, and abuse of ADs. RESULTS: A total of 1,260 interviewees completed the questionnaires. A significant percentage of interviewees were indecisive with respect to therapeutic options, ranging from 25% (analgesia) to 45% (artificial feeding). There was no connection to health status. Apprehensions about unwanted effects of ADs were widespread, at 51%, 35%, and 43% for coercion, dictatorial reading, and abuse, respectively. CONCLUSION: A significant percentage of interviewees were unable to anticipate decisions about treatment options at the end of life. Apprehensions about negative adverse effects of ADs are widespread.

Public health relevance of Graves' orbitopathy.

CONTEXT: Disfiguring proptosis and functional impairment in patients with Graves' orbitopathy (GO) may lead to impaired earning capacity and to considerable indirect/direct costs. OBJECTIVE: The aim of the study was to investigate the public health relevance of GO. DESIGN AND SETTING: This cross-sectional study was performed between 2005 and 2009 at a multidisciplinary university orbital center. PATIENTS: A total of 310 unselected patients with GO of various degrees of severity and activity participated in the study. INTERVENTIONS: We conducted an observational study. MAIN OUTCOME MEASURES: We measured work disability and sick leave as well as the resulting indirect/direct costs of GO-specific therapies. RESULTS: Of 215 employed patients, 47 (21.9%) were temporarily work disabled, and 12 (5.6%) were permanently work disabled. Five (2.3%) had lost their jobs, and nine (4.2%) had retired early. The mean duration of sick leave was 22.3 d/yr. Compared with the German average of 11.6 d/yr, 32 (15%) patients had taken longer sick leaves. The duration of sick leave correlated with the disease severity (P = 0.015), and work disability correlated with diplopia (P < 0.001). Multivariable analysis identified diplopia as the principal predictor for work disability (odds ratio, 1.7; P < 0.001). The average costs due to sick leave and work disability ranged between 3,301€ (4,153$) and 6,683€ (8,407$) per patient per year. Direct costs were 388 ± 56€ (488 ± 70$) per patient per year and per year were higher in sight-threatening GO (1,185 ± 2,569€; 1,491 ± 3,232$) than in moderate-to-severe (373 ± 896€; 469 ± 1,127$; P = 0.013) or in mild GO (332 ± 857€; 418 ± 1,078$; P = 0.016). Total indirect costs ranged between 3,318€ (4,174$) (friction cost method) and 6,738€ (8,476$) (human capital approach). Work impairment as well as direct and indirect costs of GO significantly correlated with the scores of the internationally standardized and specific GO quality-of-life questionnaire. CONCLUSIONS: Productivity loss and a prolonged therapy for GO incur great indirect and direct costs.

Quality of life in a german graves orbitopathy population.

PURPOSE: To evaluate the validity and responsiveness of a German-language version of the disease-specific Graves orbitopathy quality-of-life questionnaire (GO-QOL). DESIGN: Prospective cross-sectional study. METHODS: At a multidisciplinary university orbital center, 310 consecutive unselected Graves orbitopathy outpatients answered the GO-QOL before undergoing complete ophthalmic and endocrine assessment. The main outcome measures were the GO-QOL and its 2 subscales, Visual Functioning and Appearance. RESULTS: The QOL scores for the subscales Visual Functioning and Appearance were (mean ± SE) 72.5 ± 1.4 and 71.3 ± 1.5, respectively. Visual Functioning and Appearance were higher in mild (82.2 ± 2.2 and 86.0 ± 17.6) than in moderate to severe (66.6 ± 1.8, p < .001, 95% CI 15.6-2.9 and 65.5 ± 25.5, P < .001, 95% CI 15.1-26.0) and in sight-threatening Graves orbitopathy (41.9 ± 9.9, P < .001, 95% CI 25.4-55.3 and 58.5 ± 9.0, P < .001, 95% CI 15.0-39.4). Visual Functioning and Appearance were also lower in active (63.3 ± 2.2 and 64.5 ± 2.2) than in inactive stages (77.0 ± 1.9; P < .001, 95% CI 7.9-19.3 and 78.3 ± 1.8, P < .001, 95% CI 8.2-19.2). Visual Functioning was 81.6 ± 1.8 in patients without and 62.4 ± 2.0 in patients with diplopia (P < .001, 95% CI 13.8-24.6). Appearance was lower in those receiving psychotherapy (64.7 ± 3.2) than in those without psychotherapy (74.6 ± 1.6, P = .005, 95% CI 3.0-16.7). Significant ceiling effects (≥15% at the highest value of the subscale) were observed for Appearance in 59 patients (19%) and for Visual Functioning in 85 patients (27%). CONCLUSION: The German-language version of the GO-QOL shows evidence of validity in Graves orbitopathy and it usefully complements ophthalmic assessment in these patients.

Survival analysis: part 15 of a series on evaluation of scientific publications.

BACKGROUND: Survival times are often used to compare treatments. Survival data are a special type of data, and therefore have to be analyzed with special methods. METHODS: We illustrate special techniques for analyzing survival times by applying them to a publication on the treatment of patients with brain tumors. The present article is based on textbooks of statistics, a selective review of the literature, and the authors' own experience. RESULTS: Survival times are analyzed with the Kaplan-Meier method, which yields two measures of interest: survival rates and the median survival time. The log-rank test is used to compare survival times across treatment groups. Cox regression is used in multivariable models. The hazard ratio, a descriptive measure for differences in survival times, is explained. CONCLUSION: If survival times are analyzed without the use of special techniques, or if the underlying assumptions are not taken into account, faulty interpretation may result. Readers of scientific publications should know these pitfalls and be able to judge for themselves whether the chosen analytical method is correct.

Multiple hypotheses testing based on ordered p values--a historical survey with applications to medical research.

Global tests and multiple test procedures are often based on ordered p values. Such procedures are available for arbitrary dependence structures as well as for specific dependence assumptions of the test statistics. Most of these procedures have been considered as global tests. Multiple test procedures can be obtained by applying the closure principle in order to control the familywise error rate, or by using the false discovery rate as a criterion for type I error rate control. We provide an overview and present examples showing the importance of these procedures in medical research. Finally, we discuss modifications when different weights for the hypotheses of interest are chosen.

Test and power considerations for multiple endpoint analyses using sequentially rejective graphical procedures.

A variety of powerful test procedures are available for the analysis of clinical trials addressing multiple objectives, such as comparing several treatments with a control, assessing the benefit of a new drug for more than one endpoint, etc. However, some of these procedures have reached a level of complexity that makes it difficult to communicate the underlying test strategies to clinical teams. Graphical approaches have been proposed instead that facilitate the derivation and communication of Bonferroni-based closed test procedures. In this paper we give a coherent description of the methodology and illustrate it with a real clinical trial example. We further discuss suitable power measures for clinical trials with multiple primary and/or secondary objectives and use a generic example to illustrate our considerations.

Multiple testing in candidate gene situations: a comparison of classical, discrete, and resampling-based procedures.

In candidate gene association studies, usually several elementary hypotheses are tested simultaneously using one particular set of data. The data normally consist of partly correlated SNP information. Every SNP can be tested for association with the disease, e.g., using the Cochran-Armitage test for trend. To account for the multiplicity of the test situation, different types of multiple testing procedures have been proposed. The question arises whether procedures taking into account the discreteness of the situation show a benefit especially in case of correlated data. We empirically evaluate several different multiple testing procedures via simulation studies using simulated correlated SNP data. We analyze FDR and FWER controlling procedures, special procedures for discrete situations, and the minP-resampling-based procedure. Within the simulation study, we examine a broad range of different gene data scenarios. We show that the main difference in the varying performance of the procedures is due to sample size. In small sample size scenarios,the minP-resampling procedure though controlling the stricter FWER even had more power than the classical FDR controlling procedures. In contrast, FDR controlling procedures led to more rejections in higher sample size scenarios.

Linear regression analysis: part 14 of a series on evaluation of scientific publications.

BACKGROUND: Regression analysis is an important statistical method for the analysis of medical data. It enables the identification and characterization of relationships among multiple factors. It also enables the identification of prognostically relevant risk factors and the calculation of risk scores for individual prognostication. METHODS: This article is based on selected textbooks of statistics, a selective review of the literature, and our own experience. RESULTS: After a brief introduction of the uni- and multivariable regression models, illustrative examples are given to explain what the important considerations are before a regression analysis is performed, and how the results should be interpreted. The reader should then be able to judge whether the method has been used correctly and interpret the results appropriately. CONCLUSION: The performance and interpretation of linear regression analysis are subject to a variety of pitfalls, which are discussed here in detail. The reader is made aware of common errors of interpretation through practical examples. Both the opportunities for applying linear regression analysis and its limitations are presented.

Choosing statistical tests: part 12 of a series on evaluation of scientific publications.

BACKGROUND: The interpretation of scientific articles often requires an understanding of the methods of inferential statistics. This article informs the reader about frequently used statistical tests and their correct application. METHODS: The most commonly used statistical tests were identified through a selective literature search on the methodology of medical research publications. These tests are discussed in this article, along with a selection of other standard methods of inferential statistics. RESULTS AND CONCLUSIONS: Readers who are acquainted not just with descriptive methods, but also with Pearson's chi-square test, Fisher's exact test, and Student's t test will be able to interpret a large proportion of medical research articles. Criteria are presented for choosing the proper statistical test to be used out of the most frequently applied tests. An algorithm and a table are provided to facilitate the selection of the appropriate test.

Judging a plethora of p-values: how to contend with the problem of multiple testing--part 10 of a series on evaluation of scientific publications.

BACKGROUND: When reading reports of medical research findings, one is usually confronted with p-values. Publications typically contain not just one p-value, but an abundance of them, mostly accompanied by the word "significant." This article is intended to help readers understand the problem of multiple p-values and how to deal with it. METHODS: When multiple p-values appear in a single study, this is usually a problem of multiple testing. A number of valid approaches are presented for dealing with the problem. This article is based on classical statistical methods as presented in many textbooks and on selected specialized literature. RESULTS: Conclusions from publications with many "significant" results should be judged with caution if the authors have not taken adequate steps to correct for multiple testing. Researchers should define the goal of their study clearly at the outset and, if possible, define a single primary endpoint a priori. If the study is of an exploratory or hypothesis-generating nature, it should be clearly stated that any positive results might be due to chance and will need to be confirmed in further targeted studies. CONCLUSIONS: It is recommended that the word "significant" be used and interpreted with care. Readers should assess articles critically with regard to the problem of multiple testing. Authors should state the number of tests that were performed. Scientific articles should be judged on their scientific merit rather than by the number of times they contain the word "significant."

Quality of life and occupational disability in endocrine orbitopathy.

BACKGROUND: In endocrine orbitopathy (EO), disfiguring proptosis and diplopia impair patients' quality of life both at home and at work. METHODS: From late 2006 to the beginning of 2008, 250 outpatients in an interdisciplinary thyroid and eye clinic filled out a questionnaire about their quality of life, occupational disability, and use of psychotherapy. 400 physicians who referred their EO patients to the clinic also participated in a survey on these issues. RESULTS: 45% of the patients complained of restrictions in their daily activities, and 38% reported impaired self-perception. 36% were on sick leave because of EO. 28% were disabled, 5% had retired early, and 3% had lost their jobs. Patients with severe EO and motility disorders were on sick leave for longer times and were more likely to be disabled. 21% underwent psychotherapy. Patients who had been on sick leave for a long time and/or were disabled were more likely to undergo psychotherapy. Among the physicians answering the survey, 75% stated that they were taking care of temporarily disabled patients, while 34% were taking care of permanently disabled patients. 38% were treating EO patients who were undergoing psychotherapy. CONCLUSIONS: These data indicate that patients with EO suffer considerable emotional stress and occupational impairment and point to the need for preventive care and rapid rehabilitation.

Confidence interval or p-value?: part 4 of a series on evaluation of scientific publications.

BACKGROUND: An understanding of p-values and confidence intervals is necessary for the evaluation of scientific articles. This article will inform the reader of the meaning and interpretation of these two statistical concepts. METHODS: The uses of these two statistical concepts and the differences between them are discussed on the basis of a selective literature search concerning the methods employed in scientific articles. RESULTS/CONCLUSIONS: P-values in scientific studies are used to determine whether a null hypothesis formulated before the performance of the study is to be accepted or rejected. In exploratory studies, p-values enable the recognition of any statistically noteworthy findings. Confidence intervals provide information about a range in which the true value lies with a certain degree of probability, as well as about the direction and strength of the demonstrated effect. This enables conclusions to be drawn about the statistical plausibility and clinical relevance of the study findings. It is often useful for both statistical measures to be reported in scientific articles, because they provide complementary types of information.

Blood rheology at term in normal pregnancy and in patients with adverse outcome events.

Plasma volume expansion of more than 1.5 l and sustainable activation of the hemostatic system that results in a steady rise of the fibrinogen/fibrin turnover are contemporary physiological events during normal pregnancy. In contrast, adverse outcome of pregnancy i.e. pre-eclampsia commonly coincide with hemo concentration and over activation of blood coagulation both of which alter blood rheology. On the basis of 4,985 consecutively recorded singleton pregnancies values range of blood rheological parameters in women with normal and complicated outcome of pregnancy at the time of their delivery were compared. Plasma viscosity (pv) was determined using KSPV 1 Fresenius and RBC aggregation (stasis: E0 and low shear: E1) using MA1-Aggregometer; Myrenne. Seventy-nine point four percent (n=3,959) had normal pregnancy outcome and 1,026 with adverse outcome of pregnancy had pre-eclampsia (8.4%; n=423), had newborn with a birth-weight < 2,500 g (9.5%; n=473), had early-birth before week 37 (9.3%; n=464), and/or were diagnosed with intra uterine growth retardation (IUGR) (5.0%; n=250). In women with normal pregnancy outcome mean (+/-SD) of pv was 1.31+/-0.09 mPa s, of E0 was 21.6+/-5.3, and of E1 was 38.4+/-7.9 while in women with adverse outcome means for rheological parameters were statistically significantly different i.e. pv: 1.32+/-0.08 mPa s; p=0.006, E0: 22.1+/-5.5; p=0.002 and E1: 39.5+/-8.5; p=0.0006. Subgroup analysis revealed statistical significant lower pv in women who either had pre term delivery or a low birth-weight child (p<0.005) as compared to women who had normal pregnancy outcome while patients with pre-eclampsia had markedly higher low shear and stasis RBC aggregation (p<0.0001). None of the rheological results at term were correlated with either maternal age (r<0.04), BMI (r<0.09), maternal weight gain until delivery (r<0.04), or fetal outcome such as APGAR-score (r<0.09) art. pH in the umbilical cord (-0.05

Adaptive designs with correlated test statistics.

In clinical trials, the collected observations such as clustered data or repeated measurements are often correlated. As a consequence, test statistics in a multistage design are correlated. Adaptive designs were originally developed for independent test statistics. We present a general framework for two-stage adaptive designs with correlated test statistics. We show that the significance level for the Bauer-Köhne design is inflated for positively correlated test statistics from a bivariate normal distribution. The decision boundary for the second stage can be modified so that type one error is controlled. This general concept is expandable to other adaptive designs. In order to use these designs, the correlation between test statistics has to be estimated. For a known covariance matrix, we show how correlation can be determined within the framework of linear mixed models. A sample size reassessment rule is proposed and evaluated for an unknown covariance matrix by simulation. As Wald test statistics in linear mixed models have independent increments, we use this property to create valid test procedures. We compare these procedures with the proposed design in our simulations.

Long term follow up after percutaneous closure of PFO in 357 patients with paradoxical embolism: Difference in occlusion systems and influence of atrial septum aneurysm.

BACKGROUND: Percutaneous transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke or TIA is an alternative to medical therapy especially in patients with atrial septal aneurysm (ASA). The differences in time to complete occlusion for various closure devices in PFO alone and PFO plus ASA are of natural interest. METHODS AND RESULTS: Between January, 1st 1998 and November, 30th 2006 percutaneous PFO closure was performed in 357 patients with a history of > or =1 paradoxical embolism using three different devices: Amplatzer PFO-(n=199), Starflex-(n=48) and Helex Occluder (n=110). All patients were assigned to a post-interventional protocol with contrast-enhanced transesophageal echocardiography (TOE) at 1 and 6 months and every 6 to 12 months in case of incomplete closure. Definite closure was confirmed in at least two consecutive TOE studies. The closure time curves between the three devices were significantly different (p=0.0072). Devices of 25 mm or less had a better occlusion rate. The difference between the closure time curves of PFO and PFO+ASA concerning each device type was significant for Helex (p=0.006) and Starflex (p=0.030). In regard to the occlusion time for large devices Helex succeeded later than Amplatzer and Starflex (p=0.0029). Concerning the cumulative follow up period of 1265 patient years the recurrence/re-event rate of cerebral and peripheral thromboembolic events was 0.7% per patient year. No relation to residual PFO shunting or to thrombus formation was seen. There were no peri-interventional technical complications. In five patients of the Starflex group thrombi were detected in the four week TOE controls. CONCLUSION: The closure rate is dependent on occluder size and type plus the occurrence of an atrial septum aneurysm.

Aesthetics and power considerations in multiple testing--a contradiction?

In this paper we discuss aesthetical concepts and requirements for reasonable multiple test procedures. Aesthetical considerations lead to logical decision patterns which are conceivable and, if possible, simple to use and to communicate. Such considerations are sometimes contradictory to the ubiquitous requirement of maximizing power for a multiple test procedure. We illustrate the necessary trade-offs with several examples. We start by considering important logical properties and then discuss three different concepts of monotonicity. Afterwards we have a closer look at the recently proposed "fallback procedure" and show that it has some less appealing properties. Finally, we investigate the distribution of the numbers of significant results with respect to both expectation and variance.

Mean maternal second-trimester hemoglobin concentration and outcome of pregnancy: a population-based study.

Both anemia and the lack of physiological maternal plasma volume expansion during the second trimester are associated with higher maternal morbidity and poor fetal outcome. Mean hemoglobin levels between the 14th and 30th gestational weeks were calculated in 4985 consecutive pregnant women and were correlated with outcome data of pregnancy. It was found that 9.4% of participants (n=3959) had normal pregnancy outcome. Mean maternal hemoglobin levels were significantly lower in women with a normal pregnancy (11.96+/-0.94 g/dL) compared with women who had adverse outcome events (preeclampsia, n=423, 12.5 +/- 1.0 g/dL, P< .0001; early birth, n=464, 12.2+/-1.01 g/dL, P< .0001; low birth weight newborn, n=473, 12.2+/-1.10 g/dL, P< .0001; intrauterine growth retardation, n=250, 12.2+/-1.0 g/dL, P< .0001). The risk for any adverse outcome event was lowest with a mean hemoglobin between 11.0 and 12.0 g/dL (odds ratio, 0.625; 95% confidence interval, 0.43-0.89) and highest between 13.0 and 15.0 g/dL (odds ratio, 2.24; 95% confidence interval, 1.54-3.31). In this population-based study from a community in Western Germany, impaired plasma volume expansion was an independent risk factor for the development of an adverse outcome of pregnancy.

Strategies for including patients recruited during interim analysis of clinical trials.

In clinical trials a periodical check of safety and efficacy data is often needed. For organizational reasons it is rarely desirable to stop a trial during such an interim analysis. Therefore, new study patients are included in the trial while the interim analysis is ongoing. Disregarding the additional information provided by these interim patients would be unsatisfactory, especially for an office of regulatory affairs. Consequently, the rules for group sequential or adaptive decisions must be adjusted to the recruitment of interim patients. In this paper, two strategies for modifying study designs to consider the analysis of interim patients are proposed.

[Decompression surgery for endocrine orbitopathy]. / Operative Entlastung bei endokriner Orbitopathie.

BACKGROUND: Endocrine orbitopathy is a common feature of autoimmune thyroid disease. The increase of pressure within the eye socket leads to proptosis and compression of the optic nerve. This results in cosmetic impairment as well as loss of vision. Apart from the medical treatment surgical decompression of the crowded orbit offers a valid therapeutic option. PATIENTS AND METHODS: 142 patients (264 orbits) were treated at the interdisciplinary orbital center, Johannes Gutenberg University Hospital, Mainz, Germany. The medial orbital wall was removed, followed by lipectomy. Indications for decompression included cosmetic reasons (196 orbits, 74.2%), dysthyroid optic neuropathy (67 orbits, 25.4%), and in one case corneal ulceration. RESULTS: A median reduction of the severity score according to the NOSPECS classification from 7 points preoperatively to 4 points 3 months after surgery was achieved (p < 0.001). Median proptosis decreased from 23 to 20 mm (p < 0.001). Intraocular pressure in upgaze dropped from 23 mmHg by 3 mmHg during the first postoperative 3 months (p < 0.001). Additionally, the influence of age, sex and smoking behavior on the operation outcome was examined. Diplopia was present in 100 patients before surgery. Of the remaining 42 patients, two patients (4.8%) complained about new-onset constant diplopia 3 months after decompression, while 22 patients (52.2%) reported inconstant/intermittent motility disorders. Squint surgery corrected diplopia. CONCLUSION: The combined transnasal-endoscopic/transpalpebral approach represents a safe and efficient method for severe endocrine orbitopathy.

Powerful short-cuts for multiple testing procedures with special reference to gatekeeping strategies.

In this paper we present a general testing principle for a class of multiple testing problems based on weighted hypotheses. Under moderate conditions, this principle leads to powerful consonant multiple testing procedures. Furthermore, short-cut versions can be derived, which simplify substantially the implementation and interpretation of the related test procedures. It is shown that many well-known multiple test procedures turn out to be special cases of this general principle. Important examples include gatekeeping procedures, which are often applied in clinical trials when primary and secondary objectives are investigated, and multiple test procedures based on hypotheses which are completely ordered by importance. We illustrate the methodology with two real clinical studies.