Erika Graf

Assessment and comparison of prognostic classification schemes for survival data

Prognostic classification schemes have often been used in medical applications, but rarely subjected to a rigorous examination of their adequacy. For survival data, the statistical methodology to assess such schemes consists mainly of a range of ad hoc approaches, and there is an alarming lack of commonly accepted standards in this field. We review these methods and develop measures of inaccuracy which may be calculated in a validation study in order to assess the usefulness of estimated patient-specific survival probabilities associated with a prognostic classification scheme. These measures are meaningful even when the estimated probabilities are misspecified, and asymptotically they are not affected by random censorship. In addition, they can be used to derive R(2)-type measures of explained residual variation. A breast cancer study will serve for illustration throughout the paper.

A marker for Stevens-Johnson syndrome ...: ethnicity matters.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions, which can be caused by a certain number of specific drugs among which is carbamazepine, an antiepileptic agent. A very strong association of carbamazepine-induced SJS with HLA-B*1502 has recently been described in the Han Chinese population. Here in, we report preliminary results from a European study (RegiSCAR) of 12 carbamazepine-induced SJS/TEN cases (nine French and three German). Among these only four had a HLA-B*1502 allele. Remarkably, these four patients had an Asian ancestry, whereas the others did not as far as we have ascertained. This shows that although the HLA region may contain important genes for SJS, the HLA-B*1502 allele is not a universal marker for this disease and that ethnicity matters.

Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study.

PURPOSE To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer. PATIENTS AND METHODS Patients (tumor size > or = 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment. RESULTS Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status. CONCLUSION A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.

Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial

IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. OBJECTIVE To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. INTERVENTIONS Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. MAIN OUTCOMES AND MEASURES The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. RESULTS Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, -3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. CONCLUSION AND RELEVANCE Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54096201.

Discrete Global but No Focal Gray Matter Volume Reductions in Unmedicated Adult Patients With Attention-Deficit/Hyperactivity Disorder

BACKGROUND Gray matter reduction mainly in the anterior cingulate cortex, the basal ganglia, and the cerebellum has been reported in attention-deficit/hyperactivity disorder (ADHD). Yet, respective data remain contradictory and inconclusive. To clarify if structural alteration in these brain areas can be verified in a large cohort of adult patients and if a history of stimulant medication has an effect on brain structure, magnetic resonance imaging was performed in the context of a clinical trial on the efficacy of group psychotherapy, clinical management, methylphenidate, and placebo (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study Trial). METHODS Between January 2007 and August 2010, 1480 patients from seven study centers across Germany, aged 18 to 58, were prescreened; 518 were assessed for eligibility; 433 were randomized; and 187 were eligible for neuroimaging. The control group included 121 healthy volunteers. Structural magnetic resonance imaging data sets were acquired. Following strict quality control, 131 patient and 95 control data sets could be analyzed. All patients were unmedicated for at least 6 months. The established method of voxel-based morphometry (VBM8 segmentation and diffeomorphic anatomical registration through exponentiated lie normalization) was used to assess global and regional brain volumes. RESULTS Patients displayed subtle global cerebral volume reductions. There was no evidence of regional gray matter volume abnormalities. The inattentive ADHD subtype was linked to smaller volumes in the left dorsolateral prefrontal cortex. A history of previous medication did not modulate brain volumes. CONCLUSIONS ADHD in adulthood is associated with global rather than regional volumetric abnormalities. Previous use of stimulant medication does not seem to modify subsequent brain volumes in a significant way.

An investigation on measures of explained variation in survival analysis

Two measures of explained variation for survival data have been proposed by Kom and Simon and by Schemper. In this paper, we demonstrate how these measures compare and work out the conceptual differences between them. Both compare the variance when a covariate is accounted for with the variance when it is ignored, but only the second incorporates differences between observed and fitted outcomes. First, the relationship between both measures is studied for the situation without censoring. It turns out that considering the explained variation as a process in time is helpful in this context as well as in its own right. Censoring is incorporated quite differently for the two measures. We illustrate the points made by examples of fictitious data and a study on the treatment of breast cancer.

Die Bedeutung des Vorliegens einer Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS) bei Müttern für die Behandlung ihrer Kinder mit ADHS - Überblick und Skizze des Studienprotokolls einer multizentrischen randomisierten kontrollierten Psychotherapiestudie

Given its high heritability, ADHD frequently affects both children and their parents. In addition to co-morbid psychiatric disorders, adults with ADHD often complain of psychosocial difficulties, including family conflicts and poor parenting skills. Inconsistent childrearing practices and parent-child conflicts negatively affect the course of ADHD in children. Moreover, in the case of parental ADHD, the efficacy of parent training as part of the treatment for the childs ADHD seems to be reduced. This article presents a review of the impact of ADHD in mothers on the treatment of their ADHD children. Subsequently, the study protocol of a randomized controlled multi-centre trial to resolve the question of the efficacy of combined treatment of mothers and children is outlined. The main objective of the study is to evaluate whether the treatment of maternal ADHD enhances the efficacy of subsequent parent training as part of the treatment of ADHD in their children. 144 mother-child-pairs (both affected by ADHD according to DSM-IV criteria) are allocated to the trial. Mothers are randomized either to the treatment group (cognitive-behavioural group psychotherapy in combination with open methylphenidate treatment (Medikinet retard) titrated upward individually until the maximum dose of 1.3 mg/kg/day) or to the control group (supportive counselling). After 13 weeks of treatment individualised parent training is administered to both groups of mothers. Treatment comparisons of the primary endpoint (externalizing symptoms in the children) will be performed within a linear regression model.Zusammenfassung: Die ADHS weist eine hohe Erblichkeit auf. Kinder mit ADHS haben deswegen haufiger auch betroffene Eltern. Im Erwachsenenalter ist die Storung gekennzeichnet durch hohe Komorbiditatsraten und psychosoziale Beeintrachtigungen, die sich auch negativ auf Familienklima und erzieherische Kompetenzen auswirken. Inkonsistente Erziehungspraktiken und haufige Eltern-Kind-Konflikte tragen zur Stabilisierung der Storung bei Kindern bei. Es gibt auch Hinweise darauf, dass bei Vorliegen einer ADHS auf Elternseite die Wirksamkeit psychosozialer Interventionen zur Behandlung der ADHS des Kindes vermindert ist. Im Artikel wird ein Uberblick uber die Bedeutung des Vorliegens einer ADHS bei Muttern fur die Behandlung ihrer Kinder mit ADHS gegeben. Im Anschluss wird das Studienprotokoll einer kontrollierten randomisierten Behandlungsstudie zur Fragestellung skizziert, ob die Behandlung der ADHS der Mutter die Wirksamkeit eines Elterntrainings zur Behandlung der ADHS des Kindes erhoht. 144 Mutter-Kind-Paare (...

Planung einer klinischen Studie: Wie viele Patienten sind notwendig?

Die Grose einer klinischen Studie, d.h. die Anzahl der Patienten, die aufgenommen werden sollen — auch Fallzahl oder Stichprobenumfang genannt — ist ganz entscheidend fur die Aussagekraft einer Studie. Sie sollte vor Beginn der Studie festgelegt und mit Begrundung im Studienprotokoll festgehalten werden. In diesem Kapitel wird zunachst anhand eines fiktiven Beispiels die Zielsetzung der Fallzahlplanung erlautert. Grundlegende statistische Schlussweisen bieten den geeigneten Rahmen, um diese Ziele formal darzustellen und letztlich zu konkreten Formeln fur die Bestimmung des geeigneten Stichprobenumfangs fur eine klinische Studie zu gelangen. Die Fallzahlplanung wird im Folgenden an Beispielen von Studien mit unterschiedlichen Zielkriterien erlautert, die zum Teil bereits in anderen Kapiteln dargestellt wurden.

Goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with breast cancer. GABG trial IV-B-93

588 Background: The role of medical ablation after adjuvant chemotherapy in endocrine sensitive or non-sensitive tumors is not yet clearly defined. METHODS We initiated a prospective, randomized multicenter study comparing goserelin (3.6 mg every 28 days for 2 years) and control after adjuvant chemotherapy consisting of three cycles of CMF (500/40/600 mg/m2, i.v. on days 1, 8 q 29) in patients with 0-3+ lymph nodes (LN) and four cycles of EC (90/600 mg/m2, i.v. day 1 q 22) followed by 3 x CMF in patients with 4-9+ LN. At first only patients with hormone receptor (HR)-negative breast cancer were included. However, the study was extended to patients with HR-positive breast cancer and 1-9+ LN, when the ZEBRA study was closed. RESULTS 776 patients were included (goserelin: n=384; control: n=392), 60% had negative HR, 40% were LN-, 23% had 4-9+ LN; 30% of the patients were 40 years or younger, and 60% received breast conserving surgery. 215 events were observed after a median follow-up of 4.7 years. The first event of failure (goserelin vs control) was an isolated locoregional recurrence (43 vs 29), a distant failure (59 vs 82) and death without previous recurrence (0 vs 2). Five-year event-free survival rates were 71.3% (95% confidence interval (CI), 66.3% to 76.3%) and 67.6% (95% CI, 62.2% to 73.0%) in the goserelin and in the control group, respectively. The estimated hazard ratio of goserelin vs control was 0.92 (95% CI 0.70 to 1.21; P > 0.5) indicating no long-term benefit of goserelin in these patients. In an analysis restricted to LN+ patients, there was no indication of a differential treatment effect in HR+ as compared to HR- patients. CONCLUSIONS The results of this study do not support the use of a GnRH analogue after adjuvant chemotherapy in premenopausal patients with breast cancer. [Table: see text].

Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms: A Randomized Controlled Trial

Background and Purpose— Endovascular embolization of intracranial aneurysms with hydrogel-coated coils lowers the risk of major recurrence, but technical limitations (coil stiffness and time restriction for placement) have prevented their wider clinical use. We aimed to assess the efficacy of softer, second-generation hydrogel coils. Methods— A randomized controlled trial was conducted at 22 centers in France and Germany. Patients aged 18 to 75 years with untreated ruptured or unruptured intracranial aneurysms measuring 4 to 12 mm in diameter were eligible and randomized (1:1 using a web-based system, stratified by rupture status) to coiling with either second-generation hydrogel coils or bare platinum coils. Assist devices were allowed as clinically required. Independent imaging core laboratory was masked to allocation. Primary end point was a composite outcome measure including major aneurysm recurrence, aneurysm retreatment, morbidity that prevented angiographic controls, and any death during treatment and follow-up. Data were analyzed as randomized. Results— Randomization began on October 15, 2009, and stopped on January 31, 2014, after 513 patients (hydrogel, n=256; bare platinum, n=257); 20 patients were excluded for missing informed consent and 9 for treatment-related criteria. Four hundred eighty-four patients (hydrogel, n=243; bare platinum, n=241) were included in the analysis; 208 (43%) were treated for ruptured aneurysms. Final end point data were available for 456 patients. Forty-five out of 226 (19.9%) patients in the hydrogel group and 66/230 (28.7%) in the control group had an unfavorable composite primary outcome, giving a statistically significant reduction in the proportion of an unfavorable composite primary outcome with hydrogel coils—adjusted for rupture status—of 8.4% (95% confidence interval, 0.5–16.2; P=0.036). Adverse and serious adverse events were evenly distributed between groups. Conclusions— Our results suggest that endovascular coil embolization with second-generation hydrogel coils may reduce the rate of unfavorable outcome events in patients with small- and medium-sized intracranial aneurysms. Clinical Trial Registration— URL: https://www.drks.de/drks_web/. Unique identifier: DRKS00003132.