Explained variation and degrees of necessity and of sufficiency for competing risks survival data.

In this contribution, the Schemper-Henderson measure of explained variation for survival outcomes is extended to accommodate competing events (CEs) in addition to events of interest. The extension is achieved by moving from the unconditional and conditional survival functions of the original measure to unconditional and conditional cumulative incidence functions, the latter obtained, for example, from Fine and Gray models. In the absence of CEs, the original measure is obtained as a special case. We define explained variation on the population level and provide two different types of estimates. Recently, the authors have achieved a multiplicative decomposition of explained variation into degrees of necessity and degrees of sufficiency. These measures are also extended to the case of competing risks survival data. A SAS macro and an R function are provided to facilitate application. Interesting empirical properties of the measures are explored on the population level and by an extensive simulation study. Advantages of the approach are exemplified by an Austrian study of breast cancer with a high proportion of CEs.

Degrees of necessity and of sufficiency: Further results and extensions, with an application to covid-19 mortality in Austria.

The purpose of this paper is to extend to ordinal and nominal outcomes the measures of degree of necessity and of sufficiency defined by the authors for dichotomous and survival outcomes in a previous paper. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. The degrees of necessity and sufficiency, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic regression models; the measures, however, do not require any particular model. In addition, we study in detail the relationship between the proposed measures and the related explained variation summary for dichotomous outcomes, which are the common root for the developments for ordinal, nominal, and survival outcomes. We introduce and analyze the Austrian covid-19 data, with the aim of quantifying effects of age and other potentially prognostic factors on covid-19 mortality. This is achieved by standard regression methods but also in terms of the newly proposed measures. It is shown how they complement the toolbox of prognostic factor studies, in particular when comparing the importance of prognostic factors of different types. While the full model's degree of necessity is extremely high (0.933), its low degree of sufficiency (0.179) is responsible for the low proportion of explained variation (0.193).

Quantifying degrees of necessity and of sufficiency in cause-effect relationships with dichotomous and survival outcomes.

We suggest measures to quantify the degrees of necessity and of sufficiency of prognostic factors for dichotomous and for survival outcomes. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. Necessity and sufficiency can be seen as the two faces of causation, and this symmetry and equal relevance are reflected by the suggested measures. The measures provide an approximate, in some cases an exact, multiplicative decomposition of explained variation as defined by Schemper and Henderson for censored survival and for dichotomous outcomes. The measures, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic or Cox regression models; the measures, however, do not require any particular model. The measures of the degree of necessity implicitly generalize the established attributable fraction or risk for dichotomous prognostic factors and dichotomous outcomes to continuous prognostic factors and to survival outcomes. In a setting with multiple prognostic factors, they provide marginal and partial results akin to marginal and partial odds and hazard ratios from multiple logistic and Cox regression. Properties of the measures are explored by an extensive simulation study. Their application is demonstrated by three typical real data examples.

Explained variation in shared frailty models.

Explained variation measures the relative gain in predictive accuracy when prediction based on prognostic factors replaces unconditional prediction. The factors may be measured on different scales or may be of different types (dichotomous, qualitative, or continuous). Thus, explained variation permits to establish a ranking of the importance of factors, even if predictive accuracy is too low to be helpful in clinical practice. In this contribution, the explained variation measure by Schemper and Henderson (2000) is extended to accommodate random factors, such as center effects in multicenter studies. This permits a direct comparison of the importance of centers and of other prognostic factors. We develop this extension for a shared frailty Cox model and provide an SAS macro and an R function to facilitate its application. Interesting empirical properties of the variation explained by a random factor are explored by a Monte Carlo study. Advantages of the approach are exemplified by an Austrian multicenter study of colon cancer.

Asymptomatic Severe Aortic Stenosis in the Elderly.

OBJECTIVES: This study sought to assess the natural history and optimal timing of surgery in elderly patients with severe asymptomatic aortic stenosis (AS). BACKGROUND: AS is increasingly diagnosed in an aging population, and large numbers of elderly patients are undergoing aortic valve procedures. However, the average age of patients represented in most natural history studies on AS is between 60 and 70 years. METHODS: A total of 103 consecutive patients >70 years of age (51 female; mean age 77 ± 5 years) with asymptomatic severe AS (peak aortic jet velocity [AV-Vel] 4.7 ± 0.6 m/s) were prospectively followed. RESULTS: During follow-up, 91 events occurred, including an indication for aortic valve replacement in 82 patients and cardiac deaths in 9, respectively. Event-free survival was 73%, 43%, 23%, and 16% at 1, 2, 3, and 4 years, respectively. Physical mobility was impaired in 29% of the patients, and symptom onset was severe (New York Heart Association functional class ≥III) in 43% of those who developed symptoms. Patients with AV-Vel ≥5.0 m/s had event-free survival rates of 21% and 6% at 2 and 4 years, respectively, compared with 57% and 23% for patients with AV-Vel <5.0 m/s (p < 0.001). Seventy-one patients underwent aortic valve replacement, and post-operative survival was 89% and 77% after 1 and 3 years, respectively. CONCLUSIONS: In elderly patients with severe but asymptomatic AS, mild symptoms may be difficult to detect, particularly when mobility is impaired and severe symptom onset is common, warranting close clinical follow-up. Furthermore, a very high event rate can be expected, and cardiac deaths are not infrequent. Thus, elective aortic valve procedures may be considered in selected elderly patients at low procedural risk.

Role of a heart valve clinic programme in the management of patients with aortic stenosis.

AIMS: We sought to assess the efficacy of a heart valve clinic (HVC) follow-up programme for patients with severe aortic stenosis (AS). METHODS AND RESULTS: Three hundred and eighty-eight consecutive patients with AS (age 71 ± 10 years; aortic-jet velocity 5.1 ± 0.6 m/s) and an indication for aortic valve replacement (AVR) were included. Of these, 290 patients presented with an indication for surgery at their first visit at the HVC and 98 asymptomatic patients who had been enrolled in an HVC monitoring programme developed indications for surgery during follow-up. Time to symptom detection was significantly longer in patients that presented with symptoms at baseline (352 ± 471 days) than in patients followed in the HVC (76 ± 75 days, P < 0.001). Despite being educated to recognize and promptly report new symptoms, 77 of the 98 patients in the HVC programme waited until the next scheduled consultation to report them. Severe symptom onset (NYHA or CCS Class ≥III) was present in 61% of patients being symptomatic at the initial visit and in 34% of patients in the HVC programme (P < 0.001). CONCLUSION: Delays in referral and symptom reporting as well as symptom denial are common in patients with AS. These findings support the concept of risk stratification to identify patients who may benefit from elective surgery. A structured HVC programme results in the detection of symptoms at an earlier and less severe stage and thus in an optimized timing of surgery.

FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors.

The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ≥1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ≥1:40, mostly low-to-moderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ≥1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was -0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens.

Weight and body mass index (BMI): current data for Austrian boys and girls aged 4 to under 19 years.

BACKGROUND: BMI reference charts are widely used to diagnose overweight, obesity and underweight in children and adolescents. AIM: To provide up-to-date national reference values for Austria. METHODS: A cross-sectional sample of over 14 500 children and adolescents (4-19 years) stratified by provinces according to age- and sex-specific population proportions was drawn via schooling institutions (kindergartens, schools and vocational colleges). The generalized additive models for location, scale and shape were used for a flexible estimation of percentile curves. RESULTS: Austrian boys and girls have higher average weight compared with previous prevalence data. BMI centiles matching BMI values at age 18 years, which are used for defining thinness, overweight and obesity in adults, were calculated. In Austria, using reference values as thresholds, ∼18% of boys and 12% of girls are overweight (with thresholds passing through BMI 25.00-29.99 kg/m(2) in adults) and 5% of boys and 3% of girls are obese (with thresholds passing through BMI ≥30.00 kg/m(2) in adults). CONCLUSION: Overweight and obesity are common in Austria and their prevalence is increasing (using the same IOTF reference for international comparison). Up-to-date national BMI reference values are provided to classify children and adolescents according to the proposed overweight and obesity thresholds.

Non-parametric estimation of relative risk in survival and associated tests.

We extend the Tarone and Ware scheme of weighted log-rank tests to cover the associated weighted Mantel-Haenszel estimators of relative risk. Weighting functions previously employed are critically reviewed. The notion of an average hazard ratio is defined and its connection to the effect size measure P(Y > X) is emphasized. The connection makes estimation of P(Y > X) possible also under censoring. Two members of the extended Tarone-Ware scheme accomplish the estimation of intuitively interpretable average hazard ratios, also under censoring and time-varying relative risk which is achieved by an inverse probability of censoring weighting. The empirical properties of the members of the extended Tarone-Ware scheme are demonstrated by a Monte Carlo study. The differential role of the weighting functions considered is illustrated by a comparative analysis of four real data sets.

Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study.

Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20°C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 ± 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 ± 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 ± 3.6 vs 4.8 ± 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 ± 2.8 (ENF/mm ± SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20°C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling.

Estimating the correlation of bivariate failure times under censoring.

The analysis of correlations within pairs of survival times is of interest to many research topics in medicine, such as the correlation of survival-type endpoints of twins, the correlation of times till failure in paired organs, or the correlation of survival time with a surrogate endpoint. The dependence of such times is assumed monotonic and thus quantification by rank correlation coefficients appropriate. The typical censoring of such times requires more involved methods of estimation and inference as have been developed in recent years. The paper focuses on semiparametric approaches, and in particular on the normal copula-based estimation of Spearman correlation coefficients. The copula approach, often presented for a mathematically inclined readership, is reviewed from the viewpoint of an applied statistician. As an alternative to the maximum likelihood methodology for the normal copula approach (NCE) we introduce an iterative multiple imputation (IMI) method which requires only about 0.05% of the computing time of NCE, without sacrificing statistical performance. For IMI, survival probabilities at death or censoring times are first transformed to normal deviates. Then, those deviates that relate to censored times are iteratively augmented, by using conditional multiple imputation, until convergence is obtained for the normal scores rank correlation, which is similar to Spearman's rank correlation. Statistical properties of NCE and IMI are compared by means of a Monte Carlo study and by means of three real data sets, which also give an impression of the typical range of applications, and of their problems.

Austrian height and body proportion references for children aged 4 to under 19 years.

BACKGROUND: Previous studies have demonstrated differences between national and the WHO reference curves in children older than 5 years. Moreover, reference curves for body proportions (sitting height, subischial leg length and their ratio) based on state-of-the-art statistics are not available. AIM: To develop reference curves for height and body proportions for use in Austria and compare the curves with WHO reference curves. To estimate and statistically investigate extreme percentiles. SUBJECTS AND METHODS: A sample of ∼14 500 children between 4-19 years of age was drawn via schooling institutions, stratified by provinces according to age- and sex-specific population proportions. GAMLSS models were used for a flexible estimation of percentile curves. RESULTS AND CONCLUSIONS: After the age of 5 years national reference curves are more suitable than the WHO reference curves for clinical use in Austria. These height curves are very similar to the German reference curves published recently. Therefore, these reference curves for criteria of body proportions are recommended for use in other populations. Further validation studies are needed to establish whether the recently recommended -2.5 and -3.0 SD for height are a sensitive and specific cut-off in the diagnostic work-up for children with a suspected growth disorder using this new Austrian height chart.

Outcome of combined stenotic and regurgitant aortic valve disease.

OBJECTIVES: This study sought to describe the natural history of combined stenotic and regurgitant aortic valve disease. BACKGROUND: Data on outcome and prognostic factors in combined aortic valve disease are scarce. METHODS: This study prospectively followed 71 consecutive asymptomatic patients (21 women, age 52 ± 17 years) with at least moderate aortic stenosis in combination with at least moderate aortic regurgitation and preserved left ventricular function (ejection fraction ≥55%). RESULTS: During a median potential follow-up of 8.9 years, 50 patients developed an indication for aortic valve replacement and no cardiac deaths were observed. Overall event rates were high with an event-free survival for the entire patient population of 82 ± 5%, 62 ± 6%, 49 ± 6%, 33 ± 6%, and 19 ± 5% at 1, 2, 3, 4, and 6 years, respectively. There was 1 operative and no post-operative deaths. Peak aortic jet velocity (AV-Vel) independently predicted event-free survival. Patients with an AV-Vel between 3 and 3.9 m/s had an event-free survival of 94 ± 4%, 88 ± 6%, 65 ± 9%, and 51 ± 9% after 1, 2, 4, and 6 years, respectively, compared with 92 ± 4%, 67 ± 7%, 38 ± 8%, and 12 ± 6% for patients with an AV-Vel between 4 and 4.9 m/s and 67 ± 8%, 39 ± 10%, 17 ± 9%, and 0% for patients with an AV-Vel ≥5 m/s (p < 0.0001). CONCLUSIONS: Asymptomatic patients with combined aortic valve disease can be safely followed until surgical criteria defined for aortic stenosis, aortic regurgitation, or the aorta are reached. However, high event rates can be expected even in younger patients and those with only moderate disease. AV-Vel, which reflects both stenosis and regurgitant severity, provides an objective and easily assessable predictive parameter.

Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension.

BACKGROUND: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. METHODS: Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects. RESULTS: The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. CONCLUSION: First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

Evaluation of diagnostic and treatment approaches towards acute dyspnea in a palliative care setting among medical students at the University of Vienna.

BACKGROUND: Dyspnea is common in advanced cancer patients with opioids as first line treatment. OBJECTIVES: To evaluate the level of knowledge about diagnosis and treatment of dyspnea in palliative care patients among 4th year students. METHODS: A case report was distributed to the students describing acute dyspnea in a lung cancer patient. Students were asked to rank their diagnosis and treatment options by importance. RESULTS: 633 medical students in their 4th year attended a seminar about palliative care. Of these, 423 (77%) completed the case report. The most frequent diagnostic option was measuring patient's oxygen saturation (n = 388), followed by auscultation (n = 339). As treatment options, students chose the delivery of oxygen (n = 393) as most important. The application of opioids was suggested by a total of 138 students. CONCLUSION: Although students did not have practical skills in treating advanced cancer patients with acute dyspnea, 32.6% would suggest an opioid as treatment option.

hVps37A Status affects prognosis and cetuximab sensitivity in ovarian cancer.

PURPOSE: Although prognostic and predictive factors in ovarian cancer have been extensively studied for decades, only few have been identified and introduced to clinical practice. Here, we evaluate hVps37A (HCRP1) as a possible novel predictive marker for ovarian cancer. hVps37A was originally described as a member of the membrane-trafficking ESCRT-I complex mediating the internalization and degradation of ubiquitinated membrane receptors. EXPERIMENTAL DESIGN: We analyzed an ovarian cancer tissue microarray for HCRP1, EGFR, and HER2 expression. We used a tetracycline inducible ovarian cancer cell culture model to show the effects of hVps37A knockdown in vitro and in vivo. In addition, we studied the effects of epidermal growth factor receptor (EGFR) inhibitors cetuximab and lapatinib on ovarian cancer cells under conditions of hVps37A knockdown. RESULTS: We find that hVps37A is significantly downregulated in ovarian cancer and modifies the prognostic value of EGFR and HER2 expression. In addition, hVps37A downregulation in ovarian cancer cells leads to cytoplasmic pEGFR retention and hyperactivation of downstream pathways and is associated with enhanced xenograft growth in nude mice and invasion of the collagen matrix. Furthermore, due to subsequent sustained Akt- and MAPK-pathway activation, hVps37A-deficient cells become irresponsive to inhibition by the therapeutic antibody cetuximab. CONCLUSION: We propose that hVps37A status could become a novel prognostic and therapeutic marker for EGFR or HER2 driven tumors.

Computed tomography-based evaluation of template (NobelGuide™)-guided implant positions: a prospective radiological study.

OBJECTIVES: This prospective study was intended to evaluate the overall deviation in a clinical treatment setting to provide for quantification of the potential impairment of treatment safety and reliability with computer-assisted, template-guided transgingival implantation. MATERIAL AND METHODS: The patient population enrolled (male/female=10/8) presented with partially dentate and edentulous maxillae and mandibles. Overall, 86 implants were placed by two experienced dental surgeons strictly following the NobelGuide™ protocol for template-guided implantation. All patients had a postoperative computed tomography (CT) with identical settings to the preoperative examination. Using the triple scan technique, pre- and postoperative CT data were merged in the Procera planning software, a newly developed procedure - initially presented in 2007 allowing measurement of the deviations at implant shoulder and apex. RESULTS: The deviations measured were an average of 0.43 mm (bucco-lingual), 0.46 mm (mesio-distal) and 0.53 mm (depth) at the level of the implant shoulder and slightly higher at the implant apex with an average of 0.7 mm (bucco-lingual), 0.63 mm (mesio-distal) and 0.52 mm (depth). The maximum deviation of 2.02 mm was encountered in the corono-apical direction. Significantly lower deviations were seen for implants in the anterior region vs. the posterior tooth region (P<0.01, 0.31 vs. 0.5 mm), and deviations were also significantly lower in the mandible than in the maxilla (P=0.04, 0.36 vs. 0.45 mm) in the mesio-distal direction. Moreover, a significant correlation between deviation and mucosal thickness was seen and a learning effect was found over the time period of performance of the surgical procedures. CONCLUSION: Template-guided implantation will ensure reliable transfer of preoperative computer-assisted planning into surgical practice. With regard to the required verification of treatment reliability of an implantation system with flapless access, all maximum deviations measured in this clinical study were within the safety margins recommended by the planning software.

Gene selection in microarray survival studies under possibly non-proportional hazards.

MOTIVATION: Univariate Cox regression (COX) is often used to select genes possibly linked to survival. With non-proportional hazards (NPH), COX could lead to under- or over-estimation of effects. The effect size measure c=P(T(1)

Natural history of very severe aortic stenosis.

BACKGROUND: We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. METHODS AND RESULTS: We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67 + or - 16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) > or = 5.0 m/s (average AV-Vel, 5.37 + or - 0.35 m/s; valve area, 0.63 + or - 0.12 cm(2)). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel > or = 5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel > or = 5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). CONCLUSIONS: Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.