Publications by Amke Caliebe
Moritz JD, Hoffmann B, Sehr D, Keil K, Eggerking J, Groth G, Caliebe A, Dischinger J, Heller M, Bolte H.
Evaluation of Ultra-Low Dose CT in the Diagnosis of Pediatric-Like Fractures Using an Experimental Animal Study.Korean J Radiol,
13 (2012), 165-73.
[abstract]
Abstract:
Ultra-low dose CT provides the feasibility of a significant dose reduction, still allowing sufficient diagnostics of pediatric-like fractures.
Broch O, Renner J, Gruenewald M, Meybohm P, Schöttler J, Caliebe A, Steinfath M, Malbrain M, Bein B.
A comparison of the Nexfin(®) and transcardiopulmonary thermodilution to estimate cardiac output during coronary artery surgery.Anaesthesia,
(2012).
[abstract]
Abstract:
The newly introduced Nexfin(®) device allows analysis of the blood pressure trace produced by a non-invasive finger cuff. We compared the cardiac output derived from the Nexfin and PiCCO, using transcardiopulmonary thermodilution, during cardiac surgery. Forty patients with preserved left ventricular function undergoing elective coronary artery bypass graft surgery were studied after induction of general anaesthesia and until discharge to the intensive care unit. There was a significant correlation between Nexfin and PiCCO before (r(2) = 0.81, p < 0.001) and after (r(2) = 0.56, p < 0.001) cardiopulmonary bypass. Bland-Altman analysis demonstrated the mean bias of Nexfin to be -0.1 (95% limits of agreement -0.6 to +0.5, percentage error 23%) and -0.1 (-0.8 to +0.6, 26%) l.min(-1) .m(-2) , before and after cardiopulmonary bypass, respectively. After a passive leg-raise was performed, there was also good correlation between the two methods, both before (r(2) = 0.72, p < 0.001) and after (r(2) = 0.76, p < 0.001) cardiopulmonary bypass. We conclude that the Nexfin is a reliable method of measuring cardiac output during and after cardiac surgery.
Willuweit S, Caliebe A, Andersen MM, Roewer L.
Y-STR Frequency Surveying Method: A critical reappraisal.Forensic Sci Int Genet,
5 (2011), 84-90.
[abstract]
Abstract:
Reasonable formalized methods to estimate the frequencies of DNA profiles generated from lineage markers have been proposed in the past years and were discussed in the forensic community. Recently, collections of population data on the frequencies of variations in Y chromosomal STR profiles have reached a new quality with the establishment of the comprehensive neatly quality-controlled reference database YHRD. Grounded on such unrivalled empirical material from hundreds of populations studies the core assumption of the Haplotype Frequency Surveying Method originally described 10 years ago can be tested and improved. Here we provide new approaches to calculate the parameters used in the frequency surveying method: a maximum likelihood estimation of the regression parameters (r(1), r(2), s(1) and s(2)) and a revised Frequency Surveying framework with variable binning and a database preprocessing to take the population sub-structure into account. We found good estimates for 11 metapopulations using both approaches and demonstrate that the statistical basis of the method is well supported and independent of the population under study. The results of the estimation process are reliable and robust if the underlying datasets are large and representative and show small average and pairwise genetic distances.
Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanché H, Junge O, Wittig M, Ellinghaus D, Flachsbart F, Wichmann HE, Meitinger T, Nikolaus S, Franke A, Krawczak M, Lathrop M, Schreiber S.
A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.Mech Ageing Dev,
132 (2011), 324-30.
[abstract]
Abstract:
We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8×10(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ɛ4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.
von Wurmb-Schwark N, Caliebe A, Schwark T, Kleindorp R, Poetsch M, Schreiber S, Nebel A.
Association of TH01 with human longevity revisited.Eur J Hum Genet,
19 (2011), 924-7.
[abstract]
Abstract:
The gene tyrosine hydroxylase 1 (TH01) has been suggested as a candidate for human longevity. A previous study has shown an association between longevity and specific alleles of the TH01 short tandem repeat (STR) polymorphism in an Italian population. This STR locus is also widely used in forensic genetics. If the TH01-longevity association could be confirmed in independent samples, this finding would have important ramifications for the use of this polymorphism in a forensic context. In the present study, we sought to replicate the previous association result by investigating 471 long-lived individuals (96-110 years) and 462 younger controls (19-75 years) from Germany. In the analyzed samples, the association between TH01 and longevity was not replicated. However, the obtained TH01 allele frequencies were consistent with published data. We observed considerable differences in the allele distribution between Germans and Italians, in particular with regard to allele 9.3, which displayed a previously undetected decreasing West-East and North-South cline across Europe. The discrepant TH01-longevity association results in Germans and Italians could therefore be due to population-specific effects. This finding highlights the need to take into consideration population genetic data when dealing with association studies.
Gruenewald M, Meybohm P, Broch O, Caliebe A, Koerner S, Renner J, Steinfath M, Bein B.
Visual evaluation of left ventricular performance predicts volume responsiveness early after resuscitation from cardiac arrest.Resuscitation,
82 (2011), 1553-7.
[abstract]
Abstract:
In post-cardiac arrest period, visual evaluation of long-axis TEE loops allows prediction of volume responsiveness with good sensitivity and reasonable specificity even by novice users, and may therefore be suitable for implementation into treatment protocols.
Kapischke M, Friedrich F, Hedderich J, Schulz T, Caliebe A.
Laparoscopic versus open appendectomy--quality of life 7 years after surgery.Langenbecks Arch Surg,
396 (2011), 69-75.
[abstract]
Abstract:
Patients after laparoscopic appendectomy show a higher degree of satisfaction with their body and their scar than patients after open appendectomy.
Wolf A, Caliebe A, Thomas NS, Ball EV, Mort M, Stenson PD, Krawczak M, Cooper DN.
Single base-pair substitutions at the translation initiation sites of human genes as a cause of inherited disease.Hum Mutat,
32 (2011), 1137–43.
[abstract]
Abstract:
A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.4-fold over-represented as compared to other missense mutations. The distance between a TIC and the next downstream in-frame ATG codon was significantly greater for genes harbouring TIC mutations than for the remainder of genes in HGMD ('control genes'). This suggests that the absence of an alternative ATG codon in the vicinity of a TIC increases the likelihood that a given TIC mutation will come to clinical attention. An additional 42 single base-pair substitutions in 37 different genes were identified in the vicinity of TICs (positions -6 to +4, comprising the so-called 'Kozak consensus sequence'). These substitutions were not evenly distributed, being significantly more abundant at position +4. Finally, contrary to our initial expectation, the match between the original TIC and the Kozak consensus sequence was significantly better (rather than worse) for genes harbouring TIC mutations than for the HGMD control genes. © 2011 Wiley-Liss, Inc.
Gruenewald M, Meybohm P, Renner J, Broch O, Caliebe A, Weiler N, Steinfath M, Scholz J, Bein B.
Effect of norepinephrine dosage and calibration frequency on accuracy of pulse contour-derived cardiac output.Crit Care,
15 (2011), R22.
[abstract]
Abstract:
ABSTRACT: INTRODUCTION: Continuous cardiac output monitoring is used for early detection of hemodynamic instability and guidance of therapy in critically ill patients. Recently, the accuracy of pulse contour-derived cardiac output (PCCO) has been questioned in different clinical situations. In this study, we examined agreement between PCCO and transcardiopulmonary thermodilution cardiac output (COTCP) in critically ill patients, with special emphasis on norepinephrine (NE) administration and the time interval between calibrations. METHODS: This prospective, observational study was performed with a sample of 73 patients (mean age, 63 ± 13 years) requiring invasive hemodynamic monitoring on a non-cardiac surgery intensive care unit. PCCO was recorded immediately before calibration by COTCP. Bland-Altman analysis was performed on data subsets comparing agreement between PCCO and COTCP according to NE dosage and the time interval between calibrations up to 24 hours. Further, central artery stiffness was calculated on the basis of the pulse pressure to stroke volume relationship. RESULTS: A total of 330 data pairs were analyzed. For all data pairs, the mean COTCP (±SD) was 8.2 ± 2.0 L/min. PCCO had a mean bias of 0.16 L/min with limits of agreement of -2.81 to 3.15 L/min (percentage error, 38%) when compared to COTCP. Whereas the bias between PCCO and COTCP was not significantly different between NE dosage categories or categories of time elapsed between calibrations, interchangeability (percentage error <30%) between methods was present only in the high NE dosage subgroup (≥0.1 μg/kg/min), as the percentage errors were 40%, 47% and 28% in the no NE, NE < 0.1 and NE ≥ 0.1 μg/kg/min subgroups, respectively. PCCO was not interchangeable with COTCP in subgroups of different calibration intervals. The high NE dosage group showed significantly increased central artery stiffness. CONCLUSIONS: This study shows that NE dosage, but not the time interval between calibrations, has an impact on the agreement between PCCO and COTCP. Only in the measurements with high NE dosage (representing the minority of measurements) was PCCO interchangeable with COTCP.
Jochens A, Caliebe A, Rösler U, Krawczak M.
Empirical evaluation reveals best fit of a logistic mutation model for human y-chromosomal microsatellites.Genetics,
189 (2011), 1403-11.
[abstract]
Abstract:
The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.
Gräsner JT, Meybohm P, Caliebe A, Böttiger BW, Wnent J, Messelken M, Jantzen T, Zeng T, Strickmann B, Bohn A, Fischer H, Scholz J, Fischer M, .
Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis.Crit Care,
15 (2011), R61.
[abstract]
Abstract:
ABSTRACT: INTRODUCTION: Mild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of-hospital cardiac arrest (OHCA). METHODS: A selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis. RESULTS: The Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05). CONCLUSIONS: PCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH.
Caliebe A, Jochens A, Krawczak M, Rösler U.
A Markov chain description of the stepwise mutation model: local and global behaviour of the allele process.J Theor Biol,
266 (2010), 336-42.
[abstract]
Abstract:
The stepwise mutation model (SMM) is a simple, widely used model to describe the evolutionary behaviour of microsatellites. We apply a Markov chain description of the SMM and derive the marginal and joint properties of this process. In addition to the standard SMM, we also consider the normalised allele process. In contrast to the standard process, the normalised process converges to a stationary distribution. We show that the marginal stationary distribution is unimodal. The standard and normalised processes capture the global and the local behaviour of the SMM, respectively.
Flachsbart F, Caliebe A, Nothnagel M, Kleindorp R, Nikolaus S, Schreiber S, Nebel A.
Depletion of potential A2M risk haplotype for Alzheimer's disease in long-lived individuals.Eur J Hum Genet,
18 (2010), 59-61.
[abstract]
Abstract:
Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*epsilon4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95-100 years) and 1040 younger individuals (aged 60-75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis.
Moritz JD, Hoffmann B, Meuser SH, Sehr DH, Caliebe A, Heller M.
[Is ultrasound equal to X-ray in pediatric fracture diagnosis?].Rofo,
182 (2010), 706-14.
[abstract]
Abstract:
PURPOSE: Ultrasound is currently not established for the diagnosis of fractures. The aim of this study was to compare ultrasound and X-ray beyond their use solely for the identification of fractures, i. e., for the detection of fracture type and dislocation for pediatric fracture diagnosis. MATERIALS AND METHODS: Limb bones of dead young pigs served as a model for pediatric bones. The fractured bones were examined with ultrasound, X-ray, and CT, which served as the gold standard. RESULTS: 162 of 248 bones were fractured. 130 fractures were identified using ultrasound, and 148 using X-ray. There were some advantages of X-ray over ultrasound in the detection of fracture type (80 correct results using X-ray, 66 correct results using ultrasound). Ultrasound, however, was superior to X-ray for dislocation identification (41 correct results using X-ray, 51 correct results using ultrasound). Both findings were not statistically significant after adjustment for multiple testing. CONCLUSION: Ultrasound not only has comparable sensitivity to that of X-ray for the identification of limb fractures but is also equally effective for the diagnosis of fracture type and dislocation. Thus, ultrasound can be used as an adequate alternative method to X-ray for pediatric fracture diagnosis.
von Wurmb-Schwark N, Schwark T, Caliebe A, Drenske C, Nikolaus S, Schreiber S, Nebel A.
Low level of the mtDNA(4977) deletion in blood of exceptionally old individuals.Mech Ageing Dev,
131 (2010), 179-84.
[abstract]
Abstract:
The common 4977-bp deletion in mitochondrial DNA (dmtDNA(4977)) occurs frequently in tissues of high oxygen demand and low mitotic activity, e.g. brain, heart and skeletal muscle, where it appears to show an age-related accumulation. Although dmtDNA(4977) can also be detected in very low amounts in fast replicating tissues such as blood, it is still unclear whether an age-dependent distribution of dmtDNA(4977) occurs in blood. In view of these uncertainties, we investigated the presence of the mutation and changes in the dmtDNA(4977) level in whole blood samples from 473 individuals who belong to two different age groups, i.e. elderly (aged 61-75 years) and long-lived individuals (LLI, aged 95-109 years). We applied a highly sensitive and reliable duplex-PCR method that allowed relative quantification of dmtDNA(4977). For validation, we additionally performed absolute quantification on a subset of samples using real time-PCR. Our results showed that the proportion of dmtDNA(4977) carriers was very similar in both groups, but that the individual mutational load was on average much lower in the nonagenarians and centenarians than in the elderly. The finding was independent of smoking habits, gender or variation in APOE and FOXO3A but could be caused by other environmental and/or genetic factors.
Caliebe A, Kleindorp R, Blanché H, Christiansen L, Puca AA, Rea IM, Slagboom E, Flachsbart F, Christensen K, Rimbach G, Schreiber S, Nebel A.
No or only population-specific effect of PON1 on human longevity: a comprehensive meta-analysis.Ageing Res Rev,
9 (2010), 238-44.
[abstract]
Abstract:
Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet).
Flachsbart F, Franke A, Kleindorp R, Caliebe A, Blanché H, Schreiber S, Nebel A.
Investigation of genetic susceptibility factors for human longevity - A targeted nonsynonymous SNP study.Mutat Res,
694 (2010), 13-9.
[abstract]
Abstract:
Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.
Kapischke M, Schulze H, Caliebe A.
Self-fixating mesh for the Lichtenstein procedure--a prestudy.Langenbecks Arch Surg,
395 (2010), 317-22.
[abstract]
Abstract:
INTRODUCTION: Secure fixation of the mesh in groin hernia repair is essential to avoid mesh dislocation. The fixation, however, is also thought to be a source of chronic postoperative pain. We tested the new self-fixating mesh Parietene progrip vs. traditional suture fixating Lichtenstein repair in a double-blinded randomized study evaluating postoperative pain and the use of analgesics. METHODS: Fifty patients were randomized into two groups: Patients of group A (24 patients) were operated with the new self-fixating Parietene progrip mesh without fixation sutures and patients of group B (26 patients) were operated with the traditional Lichtenstein repair. Postoperative course including pain and the use of analgesics were monitored. Patients were reinvestigated after 6 months regarding pain score and the amount of analgesics used during this interval. Primary end point was pain on the first operative day. RESULTS: The visual analog scale pain score showed at the first postoperative day a significantly lower level in group A than in group B (mean 17.9 vs. 32.3 mm, p = 0.03). Additionally, the cumulative dose of postoperatively required analgesics was lower in group A than in group B. The operative time in group A was significantly shorter than in group B. Six months after the operation, a trend toward a lower pain score was observed in group A, but this did not reach statistical significance. CONCLUSIONS: This is the first randomized study to show a beneficial effect of the new self-fixating mesh on pain score. According to our investigations, operative time is reduced, which is a considerable fact with regard to economic aspects as well as the beneficial aspects for the patients. A study with a larger cohort of patients should be conducted to confirm the promising results of this exploratory study.
Nebel A, Flachsbart F, Till A, Caliebe A, Blanché H, Arlt A, Häsler R, Jacobs G, Kleindorp R, Franke A, Shen B, Nikolaus S, Krawczak M, Rosenstiel P, Schreiber S.
A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians.Mech Ageing Dev,
130 (2009), 691-99.
[abstract]
Abstract:
Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the common allele (C) of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A.
Association of FOXO3A variation with human longevity confirmed in German centenarians.Proc Natl Acad Sci U S A,
106 (2009), 2700-5.
[abstract]
Abstract:
The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.
Lu TT, Lao O, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Nielsen F, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Ruether A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Kayser M, Krawczak M.
An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population.Eur J Hum Genet,
17 (2009), 967-75.
[abstract]
Abstract:
Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics advance online publication, 21 January 2009; doi:10.1038/ejhg.2008.266.
Wolf A, Millar DS, Caliebe A, Horan M, Newsway V, Kumpf D, Steinmann K, Chee IS, Lee YH, Mutirangura A, Pepe G, Rickards O, Schmidtke J, Schempp W, Chuzhanova N, Kehrer-Sawatzki H, Krawczak M, Cooper DN.
A gene conversion hotspot in the human growth hormone (GH1) gene promoter.Hum Mutat,
30 (2009), 239-47.
[abstract]
Abstract:
To assess the evolutionary importance of nonallelic (or interlocus) gene conversion for the highly polymorphic human growth hormone (GH1) gene promoter, sequence variation in this region was studied in four different ethnic groups. For 14 SNPs in the proximal GH1 promoter (535 bp), 60 different haplotypes were observed in 577 individuals (156 Britons, 116 Spaniards, 163 West-Africans, 142 Asians). Using a novel coalescence-based statistical test, significant evidence was found in the British, Spanish, and African groups for GH1 having acted as an acceptor of gene conversion, with at least one of the four paralogous GH gene promoters serving as the donor (and specifically GH2 in the Britons and Spaniards). The average gene conversion tract length was estimated to be 84 bp. A gene conversion hotspot was identified, spanning the GH1 transcriptional initiation site (positions -6 to +25). Although these findings serve to highlight the importance of gene conversion for the recent evolution of the human GH1 promoter, its relative frequency does not appear to be related simply to the presence of specific DNA sequence motifs or secondary structures, the degree of homology between GH paralogs, the distance between them, or their transcriptional orientation. The GH1 promoter was also found to be highly polymorphic in chimpanzee but not in macaque. This may reflect the lower degree of pair-wise similarity between the GH1 promoter and its paralogs in macaque (mean, 92.0%) as compared to chimpanzee (93.5%) and human (94.0%), and hence provides further support for the idea of a threshold (perhaps around 92%) below which gene conversion is reduced or abolished.
Kapischke M, Schulz T, Schipper T, Tensfeldt J, Caliebe A.
Open versus laparoscopic incisional hernia repair: something different from a meta-analysis.Surg Endosc,
22 (2008), 2251-60.
[abstract]
Abstract:
BACKGROUND: Incisional hernias after laparotomy are a large financial burden for society as well as for the patients suffering from pain and limitations of activity over time. The introduction of alloplastic materials such as polypropylene seems to improve the results. The question of whether to apply open or laparoscopic implantation of the mesh is of ongoing interest. We compare the available alloplastic materials and try to clarify the question of whether the laparoscopic procedure is superior to the conventional (open) technique based on the available randomized studies. METHODS: All available meshes for intraperitoneal and extraperitoneal implantation were described regarding their handling and their pros and cons. A database search (PubMed, Medline, Ovid, and in the secondary literature) was carried out to retrieve all randomized studies comparing laparoscopic and open hernia repair. Data were reviewed by two independent scientists for surgical and statistical design. RESULTS: The ideal mesh for a laparoscopic maintenance of abdominal wall hernias as well as the optimal fixation of the mesh has not been found yet. Recent available literature shows no evidence demonstrating the superiority of one of these meshes. The available studies found a lower infection rate, but higher occurrence of seroma for the laparoscopic procedure. The value of the different studies is reduced due to deficiency in study design and power. Guidelines for further studies are discussed to avoid surgical and statistical pitfalls. CONCLUSIONS: Laparoscopic incisional hernia repair shows, in some (randomized) studies as well as a large number of retrospective analyses and in case control studies, superiority compared to conventional hernia repair. Long-term results with a high level of evidence are not available. Additional well-designed randomized trials including long-term observation of patients are required in order to clarify a number of interesting questions.
Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Rüther A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Krawczak M, Kayser M.
Correlation between genetic and geographic structure in Europe.Curr Biol,
18 (2008), 1241-8.
[abstract]
Abstract:
Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.
Haenisch S, May K, Wegner D, Caliebe A, Cascorbi I, Siegmund W.
Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol.Pharmacogenet Genomics,
18 (2008), 357-65.
[abstract]
Abstract:
OBJECTIVES: To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump. METHODS: We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 374 nonrelated German healthy volunteers and determined the impact on duodenal mRNA and protein content of ABCC2. For functional analysis, the disposition of intravenously (30 mg) and orally administered talinolol (100 mg) was measured among 31 individuals. Moreover, the effects of rifampicin-type induction (600 mg, 8 days) of duodenal ABCC2 were quantified in 22 participants with regard to genetic polymorphisms. RESULTS: The allele frequencies were 18.3% (-24T), 21.1% (1249A), 1.4% (1446G), 0.1% (3542T), 4.5% (3563A), 34.2% (3972T), and 4.4% (4544A); carriers of -23G>A, 1457C>T, 2302C>T, 2366C>T, 3561G>A, and 4348G>A were not identified. The -24T allele was in strong linkage with 3972T, and 3563A with 4544A, whereas 1249A was weakly linked with other variant alleles. None of the single nucleotide polymorphisms investigated influenced significantly intestinal ABCC2 mRNA and protein content. The variant ABCC2 1249G>A (V417I), however, was associated with lower oral bioavailability (P=0.001), and increased residual clearance of intravenous talinolol (P=0.021). Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T>A or 4544G>A. CONCLUSION: The 1249G>A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter.
Caliebe A.
Mathematische Modelle in der Populationsgenetik.medgen,
20 (2008), 282-287.
[abstract]
Abstract:
In der mathematischen Populationsgenetik
wird der Einfluss von Selektion und Mutation
auf die zeitliche Entwicklung der genetischen
Struktur einer Population modelliert. Da alle Populationen und erst recht die für ihre
Untersuchung zur Verfügung stehenden Stichproben endlich sind, spielen die stochastischen
Aspekte der verwendeten Modelle eine
besondere Rolle. Wichtige populationsgenetische
Modelle sind das Wright-Fisher-Modell
und das Koaleszenzmodell für die Genealogie
von Stichproben sowie das „infinite alleles
model“ und das „infinite sites model“ für die darin ablaufenden Mutationsprozesse.
In mathematical population genetics, the influence
of selection and mutation on the evolution
of a population is modelled. Because all populations and particularly the samples used for their analysis are finite, the stochastic
nature of these models plays an important role. Relevant genetic models include the Wright–Fisher model and the coalescence model for the genealogy of samples, as well as the infinite alleles model and the infinite sites model for the mutation processes superimposed
upon these genealogies.
Renders L, Frisman M, Ufer M, Mosyagin I, Haenisch S, Ott U, Caliebe A, Dechant M, Braun F, Kunzendorf U, Cascorbi I.
CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients.Clin Pharmacol Ther,
81 (2007), 228-34.
[abstract]
Abstract:
It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.
Caliebe A, Hirschbiegel J.
Philipp der Kühne, Johann Ohnefurcht und der höfische Geschenkverkehr zum neuen Jahr um 1400.In: Paris, capitale des ducs de Bourgogne, Werner Paravicini, Bertrand Schnerb (Eds.), OstfildIn: Paris, capitale des ducs de Bourgogne, Werner Paravicini, Bertrand Schnerb (Eds.), Ostfildern: Thorbeckeern: Thorbecke, Beihefte der Francia,
64 (2007), 219-63.
Krawczak M, Caliebe A, Croucher PJ, Schmidtke J.
On the testing load incurred by cascade genetic carrier screening for Mendelian disorders: a brief report.Genet Test,
11 (2007), 417-9.
[abstract]
Abstract:
One criterion to decide to whom molecular genetic carrier testing should be provided is an individual's carrier risk, taking into account his or her affection status and degree of relatedness to an overt carrier. We have derived formulas to calculate the testing load incurred to a public health system following such a cascade screening strategy. While the testing load turns out to be moderate for individual diseases at meaningful risk thresholds (i.e., 1%-5%), a substantial proportion of the population would have to be tested if all known single gene disorders were to be included in a cascade screening program.
Caliebe A, Neininger R, Krawczak M, Rösler U.
On the length distribution of external branches in coalescence trees: genetic diversity within species.Theor Popul Biol,
72 (2007), 245-52.
[abstract]
Abstract:
Let Z(n) denote the length of an external branch, chosen at random from a Kingman n-coalescent. Based on a recursion for the distribution of Z(n), we show that nZ(n) converges in distribution, as n tends to infinity, to a non-negative random variable Z with density x--> 8/(2+x)(3), x>or=0. This result facilitates the study of the time to the most recent common ancestor of a randomly chosen individual and its closest relative in a given population. This time span also reflects the maximum relatedness between a single individual and the rest of the population. Therefore, it measures the uniqueness of a random individual, a central characteristic of the genetic diversity of a population.
Steffens M, Lamina C, Illig T, Bettecken T, Vogler R, Entz P, Suk EK, Toliat MR, Klopp N, Caliebe A, König IR, Köhler K, Ludemann J, Diaz Lacava A, Fimmers R, Lichtner P, Ziegler A, Wolf A, Krawczak M, Nūrnberg P, Hampe J, Schreiber S, Meitinger T, Wichmann HE, Roeder K, Wienker TF, Baur MP.
SNP-based analysis of genetic substructure in the German population.Hum Hered,
62 (2006), 20-9.
[abstract]
Abstract:
OBJECTIVE: To evaluate the relevance and necessity to account for the effects of population substructure on association studies under a case-control design in central Europe, we analysed three samples drawn from different geographic areas of Germany. Two of the three samples, POPGEN (n = 720) and SHIP (n = 709), are from north and north-east Germany, respectively, and one sample, KORA (n = 730), is from southern Germany. METHODS: Population genetic differentiation was measured by classical F-statistics for different marker sets, either consisting of genome-wide selected coding SNPs located in functional genes, or consisting of selectively neutral SNPs from 'genomic deserts'. Quantitative estimates of the degree of stratification were performed comparing the genomic control approach [Devlin B, Roeder K: Biometrics 1999;55:997-1004], structured association [Pritchard JK, Stephens M, Donnelly P: Genetics 2000;155:945-959] and sophisticated methods like random forests [Breiman L: Machine Learning 2001;45:5-32]. RESULTS: F-statistics showed that there exists a low genetic differentiation between the samples along a north-south gradient within Germany (F(ST)(KORA/POPGEN): 1.7 . 10(-4); F(ST)(KORA/SHIP): 5.4 . 10(-4); F(ST)(POPGEN/SHIP): -1.3 . 10(-5)). CONCLUSION: Although the F(ST )-values are very small, indicating a minor degree of population structure, and are too low to be detectable from methods without using prior information of subpopulation membership, such as STRUCTURE [Pritchard JK, Stephens M, Donnelly P: Genetics 2000;155:945-959], they may be a possible source for confounding due to population stratification.
Caliebe A.
Properties of the maximum a posteriori path estimator in hidden Markov models.IEEE Trans. Inform. Theory,
52 (2006), 41-51.
Kapischke M, Caliebe A, Tepel J, Schulz T, Hedderich J.
Open versus laparoscopic appendicectomy: a critical review.Surg Endosc,
20 (2006), 1060-8.
[abstract]
Abstract:
BACKGROUND: The benefit of laparoscopic appendicectomy remains unclear. We have analysed available randomised studies comparing laparoscopic and open appendicectomy regarding their clinical pitfalls and statistical relevance. METHODS: Thirty eight studies were analysed in terms of the following aspects: A. clinical problems (e.g., expertise of the surgeons, pre- and postoperative antibiotic treatment, definition of complications, blinding of outcomes) and B. statistical problems (e.g., definition of primary and secondary outcomes, power and sample size, statistical methods, confidence intervals, comparability of groups and studies). RESULTS: Most of the studies have clinical and statistical pitfalls. The most important pitfalls are the uncertain expertise of the operating surgeons, blinding, and the exploratory nature of the studies. Our analysis aims at giving useful information for the appraisal of existing studies and the conduct of further studies. It also gives some preliminary results. CONCLUSIONS: More than twenty years after Semm performed the first laparoscopic appendicectomy, it is necessary to clarify the superiority of laparoscopic or open appendectomy with well-defined, carefully designed randomised studies.
Wolf A, Caliebe A, Junge O, Krawczak M.
Forensic interpretation of Y-chromosomal DNA mixtures.Forensic Sci Int,
152 (2005), 209-13.
[abstract]
Abstract:
The mathematical concept previously introduced for the forensic interpretation of DNA mixtures using non-associated genetic markers has been adapted to the assessment of haplotypes. Such calculus is required, for example, when Y-chromosomal markers are used in forensics. In addition to outlining the general mathematical framework, we devise two approaches to its practical computational implementation, involving either the inclusion-exclusion principle of probability theory or a recursion in the number of unknown contributors invoked. The two approaches scale differently, depending upon the complexity of the case and the diversity of the markers used. The performance of Y-chromosomal microsatellites (Y-STRs) as a means of trace donor discrimination has been assessed by simulation, using the derived formulas. Based upon data from the Y-chromosomal Haplotype Reference Database (YHRD), the exclusion chance of a non-contributor is shown to vary between 95% in the case of two contributors, and 70% for five contributors. With only one additional contributor, half of all contributing suspects would yield a log-likelihood ratio in favour of donorship of 1.61 or higher, although the median drops to 0.66 with four additional contributors. It must be emphasised that these estimates of the discriminatory power of Y-STRs are likely to be conservative since the simulations involved only haplotypes known to occur in YHRD.
Caliebe A, Freitag S, Krawczak M.
Stochastische Modelle für Interaktion und Effektmodifikation.Medizinische genetik,
17 (2005), 14-9.
Caliebe A.
Representation of fixed points of a smoothing transformation.In: Mathematics and Computer Science III, editors: M. Drmota, P. Flajolet, D. Gardy, B. Gittenberger, Trends in Mathematics, Birkhäuser Verlag Basel,
(2004), 311-24.
Caliebe A, Rösler U.
Fixed points with finite variance of a smoothing transformation.Stochastic Process Appl,
107 (2003), 105-29.
Caliebe A.
Symmetric fixed points of a smoothing transformation.Adv in Appl Probab,
35 (2003), 377-94.
Caliebe A, Rösler U, Hansen UP.
A χ² test for model determination and sublevel detection in ion channel analysis.J Membr Biol,
185 (2002), 25-41.
[abstract]
Abstract:
A χ² test is proposed that provides a means of discriminating between different Markov models used for the description of a measured (patch clamp) time series. It is based on a test statistic constructed from the measured and the predicted number of transitions between the current levels. With a certain probability, this test statistic is below a threshold if the model with a reduced number of degrees of freedom is compatible with the data. A second criterion is provided by the dependence of the test statistic on the number of data points. For data generated by the alternative model it increases linearly. The applicability of this test for verifying and rejecting models is illustrated by means of time series generated by two distinct channels with different conductances and by time series generated by one channel with two conductance levels. For noisy data, a noise correction is proposed, which eliminates noise-induced false jumps that would interfere with the test. It is shown that the test can also be extended to aggregated Markov models.
Riessner T, Woelk F, Abshagen-Keunecke M, Caliebe A, Hansen UP.
A new level detector for ion channel analysis.J Membr Biol,
189 (2002), 105-18.
[abstract]
Abstract:
The algorithm proposed here for automatic level detection in noisy time series of patch-clamp current is based on the detection of jump-free sections in the time series. The detector moves along the time series and uses a chi(2) test for the detection of jumps. When a jump is detected, the mean value, the variance and the length of the preceding jump-free section are stored. A Student's t-test was employed for the assignment of detected jump-free sections to discrete levels of the Markov model and for rejection of all sections with multiple assignments. The choice of the two significance levels is based on a 3-D diagram displaying the average number of detected levels from several time series vs. the significance levels of jump detection and of level assignment. The correct one is selected out of several plateaus with integer number of levels by means of the criterion of minimum scatter or other plausibility considerations. The test has been applied to simulated data obtained from a 2-state model and a 5-state aggregated Markov model, and the influences of SNR and of gating frequency are shown. Finally, the performance of the level detector is compared with a fit-by-eye and with a fit of the amplitude histogram by a sum of gaussians. At high noise, the fit of amplitude histograms failed, whereas the other two approaches were about equal.
Caliebe A, Rösler U.
Convergence of the maximum a posteriori path estimator in hidden Markow models.IEEE Transactions on Information Theory,
48 (2002), 1750-1758.
