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Hein Putter

Publications and source records attributed to Hein Putter.

At least 19 recordsLinked to original sources
PubMed2006

Role of calcified spots detected by intravascular ultrasound in patients with ST-segment elevation acute myocardial infarction.

Electron beam computed tomographic studies have demonstrated that the extent of intracoronary calcium is related to risk of coronary events. This study was performed to gain further insight into the distribution of focal calcifications and their relation to the site of plaque rupture within the culprit artery in consecutive patients (n = 60) with acute myocardial infarction (AMI) using intravascular ultrasound imaging. Calcifications in the culprit lesion and adjacent segments were classified and counted according to their arc (< 45 degrees, 45 degrees to 90 degrees, 90 degrees to 180 degrees, > 180 degrees), length (< 1.5, 1.5 to 3.0, 3.0 to 6.0, > 6.0 mm), and dispersion (number of spots per millimeter). Calcifications at the edge of a visible rupture or ulceration were considered related to the AMI. Compared with adjacent proximal and distal segments, the culprit lesion contained more calcified spots per millimeter (0.14, 0.10, and 0.21, respectively, p < 0.05). Small calcified spots (arc < 45 degrees, length < 1.5 mm) were more common (p < 0.05). Plaque rupture or ulceration was manifest in 31 culprit lesions (52%), 14 (45%) of which contained focal calcifications. These calcified spots extended more often to 90 degrees to 180 degrees of the vessel circumference and were more often of moderate length (3 to 6 mm) compared with culprit lesions without visible plaque rupture (p < 0.05). In conclusion, culprit lesions in patients with AMI contain more and smaller calcifications compared with adjacent segments. Calcifications related to plaque rupture appear to be larger and extend over a wider arc compared with these calcified spots. Those larger calcified spots may play a role in plaque instability in a subgroup of lesions.

Calcinosis↗
PubMed2006

Factors influencing the local failure rate of radiofrequency ablation of colorectal liver metastases.

BACKGROUND: The prognosis of patients with colorectal cancer is poor, especially when there is distant metastatic disease. Local ablation of tumor by radiofrequency ablation (RFA) has emerged as a safe and effective new treatment modality, but its long-term efficacy may be hindered by renewed local tumor growth at the site of RFA. The objectives of this study were to identify risk factors for local RFA failure and to define exclusion criteria for RFA treatment of colorectal liver metastases. METHODS: A total of 199 lesions in 87 patients were ablated with RFA. Factors influencing local failure rates were identified and compared with data from the literature. RESULTS: The local failure rate was 47.2%, and the average time to local disease progression was 6.5 months. Factors that significantly correlated with increased failure rates were metachronous occurrence of liver metastases, large mean lesion size, and central tumor location. CONCLUSIONS: Because accurate electrode placement is pivotal in achieving adequate tumor necrosis, RFA should not be performed percutaneously when electrode placement is impaired. We suggest that lesions >5 cm and lesions located near great vessels or adjacent organs should be treated with open RFA, thus allowing vascular inflow occlusion and complete mobilization of the liver. Lesions that are difficult to reach by electrodes should be approached by an open procedure.

Adult↗
PubMed2006

Hemodynamic effects of long-term cardiac resynchronization therapy: analysis by pressure-volume loops.

BACKGROUND: Acute hemodynamic effects of cardiac resynchronization therapy (CRT) were reported previously, but detailed invasive studies showing hemodynamic consequences of long-term CRT are not available. METHODS AND RESULTS: We studied 22 patients scheduled for implantation of a CRT device based on conventional criteria (New York Heart Association class III or IV, left ventricular [LV] ejection fraction <35%, left bundle-branch block, and QRS duration >120 ms). During diagnostic catheterization before CRT, we acquired pressure-volume loops using conductance catheters during atrial pacing at 80, 100, 120, and 140 bpm. Studies were repeated during biventricular pacing at the same heart rates after 6 months of CRT. Our data show a significant clinical benefit of CRT (New York Heart Association class change from 3.1+/-0.5 to 2.1+/-0.8; quality-of-life score change from 44+/-12 to 31+/-16; and 6-minute hall-walk distance increased from 260+/-149 to 396+/-129 m; all P<0.001), improved LV ejection fraction (from 29+/-10% to 40+/-13%, P<0.01), decreased end-diastolic pressure (from 18+/-8 to 13+/-6 mm Hg, P<0.05), and reverse remodeling (end-diastolic volume decreased from 257+/-67 to 205+/-54 mL, P<0.01). Previously reported acute improvements in LV function remained present at 6 months: dP/dtmax increased 18%, -dP/dtmin increased 13%, and stroke work increased 34% (all P<0.01). Effects of increased heart rate were improved toward more physiological responses for LV ejection fraction, cardiac output, and dP/dtmax. Moreover, our study showed improved ventricular-arterial coupling (69% increase, P<0.01) and improved mechanical efficiency (44% increase, P<0.01). CONCLUSIONS: Hemodynamic improvements with CRT, previously shown in acute invasive studies, are maintained chronically. In addition, ventricular-arterial coupling, mechanical efficiency, and chronotropic responses are improved after 6 months of CRT. These findings may help to explain the improved functional status and exercise tolerance in patients treated with CRT.

Aged↗
PubMed2006

Estimation and prediction in a multi-state model for breast cancer.

An important aim in clinical studies in oncology is to study how treatment and prognostic factors influence the course of disease of a patient. Typically in these trials, besides overall survival, also other endpoints such as locoregional recurrence or distant metastasis are of interest. Most commonly in these situations, Cox regression models are applied for each of these endpoints separately or to composite endpoints such as disease-free survival. These approaches however fail to give insight into what happens to a patient after a first event. We re-analyzed data of 2795 patients from a breast cancer trial (EORTC 10854) by applying a multi-state model, with local recurrence, distant metastasis, and both local recurrence and distant metastasis as transient states and death as absorbing state. We used an approach where the clock is reset on entry of a new state. The influence of prognostic factors on each of the transition rates is studied, as well as the influence of the time at which intermediate events occur. The estimated transition rates between the states in the model are used to obtain predictions for patients with a given history. Formulas are developed and illustrated for these prediction probabilities for the clock reset approach.

Biometry↗
PubMed2005

Combining evidence for association from transmission disequilibrium and case-control studies using single-nucleotide polymorphisms.

The aim of the present analysis is to combine evidence for association from the two most commonly used designs in genetic association analysis, the case-control design and the transmission disequilibrium test (TDT) design. The cases here are affected offspring from nuclear families and are used in both the case-control and TDT designs. As a result, inference from these designs is not independent. We applied a simple logistic regression method for combining evidence for association from case-control and TDT designs to single-nucleotide polymorphism data purchased on a region on chromosome 3, replicate 1 of the Aipotu population. Combining the evidence from the case-control and TDT designs yielded a 5-10% reduction in the standard errors of the relative risk estimates. The authors did not know the results before the analyses were conducted.

Case-Control Studies↗
PubMed2005

How to quantify information loss due to phase ambiguity in haplotype case-control studies.

Assigning haplotypes in a case-control study is a challenging problem. We proposed a method to quantify the information loss due to missing phase information. We determined which individuals were responsible for the information loss, and calculated how much information could be gained when the ambiguous individuals could be resolved by adding additional parental information.

Case-Control Studies↗
PubMed2005

Modeling the effect of an associated single-nucleotide polymorphism in linkage studies.

For linkage analysis in affected sibling pairs, we propose a regression model to incorporate information from a disease-associated single-nucleotide polymorphism located under the linkage peak. This model can be used to study if the associated single-nucleotide polymorphism marker partly explains the original linkage peak. Two sources of information are used for performing this task, namely the genotypes of the parents and the genotypes of the siblings. We applied the methods to three significantly disease-associated single-nucleotide polymorphisms and five microsatellite markers at the end of chromosome 3 of replicate 1 of Aipotu population. Two out of five of the microsatellite markers showed a LOD score higher than 3. The question to be answered was whether one of the single-nucleotide polymorphisms partly explains these high LOD scores. We did not have the answers when we analyzed the data.

Chromosomes, Human, Pair 3↗
PubMed2005

Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism.

PURPOSE: To retrospectively quantify right ventricular dysfunction (RVD) and the pulmonary artery obstruction index at helical computed tomography (CT) on the basis of various criteria proposed in the literature and to assess the predictive value of these CT parameters for mortality within 3 months after the initial diagnosis of pulmonary embolism (PE). MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was not required for retrospective study. In 120 consecutive patients (55 men, 65 women; mean age +/- standard deviation, 59 years +/- 18) with proved PE, two readers assessed the extent of RVD by quantifying the ratio of the right ventricle to left ventricle short-axis diameters (RV/LV) and the pulmonary artery to ascending aorta diameters, the shape of the interventricular septum, and the extent of obstruction to the pulmonary artery circulation on helical CT images, which were blinded for clinical outcome in consensus reading. Regression analysis was used to correlate these parameters with patient outcome. RESULTS: CT signs of RVD (RV/LV ratio, >1.0) were seen in 69 patients (57.5%). During follow-up, seven patients died of PE. Both the RV/LV ratio and the obstruction index were shown to be significant risk factors for mortality within 3 months (P = .04 and .01, respectively). No such relationship was found for the ratio of the pulmonary artery to ascending aorta diameters (P = .66) or for the shape of the interventricular septum (P = .20). The positive predictive value for PE-related mortality with an RV/LV ratio greater than 1.0 was 10.1% (95% confidence interval [CI]: 2.9%, 17.4%). The negative predictive value for an uneventful outcome with an RV/LV ratio of 1.0 or less was 100% (95% CI: 94.3%, 100%). There was a 11.2-fold increased risk of dying of PE for patients with an obstruction index of 40% or higher (95% CI: 1.3, 93.6). CONCLUSION: Markers of RVD and pulmonary vascular obstruction, assessed with helical CT at baseline, help predict mortality during follow-up.

Acute Disease↗
PubMed2005

Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.

BACKGROUND: Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy). PATIENTS AND METHODS: The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990). RESULTS: Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007). CONCLUSION: Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.

Female↗
PubMed2005

Mechanical bowel preparation or not? Outcome of a multicenter, randomized trial in elective open colon surgery.

PURPOSE: Mechanical bowel preparation is common practice in elective colon surgery. In recent literature the value of this procedure is under discussion. To verify the value of mechanical bowel preparation in elective open colon surgery, a randomized clinical trial was conducted. METHODS: During a prospective, multicenter, randomized study, 250 patients undergoing elective open colon surgery were randomized between receiving mechanical bowel preparation with polyethylene glycol (PEG group, 125 patients) and having a normal meal preoperatively (normal meal preoperatively group, 125 patients). Outcome parameters were wound infection with bacterial results of intraoperative swabs and anastomotic leak. RESULTS: In the polyethylene glycol group there were a total of nine wound infections (7.2 percent) and seven anastomotic leaks (5.6 percent) compared with seven wound infections (5.6 percent) (P = 0.61) and six anastomotic leaks (4.8 percent) (P = 0.78) in the normal meal preoperatively group. Bacterial results showed 52 percent sterile subcutis swabs in the PEG group and 63 percent sterile subcutis swabs in the normal meal preoperatively group (P = 0.11). CONCLUSION: In the present study we could not detect a difference in outcome parameters between patients receiving mechanical bowel preparation in elective open colon surgery and patients without preoperative treatment of the bowel. The present study, although underpowered, did not show a difference in the primary outcome of bacterial wound cultures between patients receiving preoperative mechanical bowel preparation and patients receiving no preoperative bowel treatment. We conclude that there may be no need to continue the use of mechanical bowel preparation in elective open colon surgery.

Adult↗
PubMed2005

The impact of diagnosis and treatment of rectal cancer on paid and unpaid labor.

PURPOSE: This study was designed to describe the consequences of diagnosis and treatment of rectal cancer for paid and unpaid labor over time and to identify sociodemographic-related factors, treatment-related factors, and quality of life-related factors associated with paid and unpaid labor. METHODS: Data were assessed prospectively in two samples of patients with primary rectal cancer, participating in a multicenter clinical trial, who were randomized to receive surgery with or without 5 x 5-Gy preoperative radiotherapy. For paid labor, 292 patients who indicated paid labor before treatment filled out quality of life questionnaires, which included questions on paid labor at 3, 6, 12, 18, and 24 months after surgery. For unpaid labor, another sample of 92 patients also filled out the Health and Labor questionnaire, which included questions on unpaid labor, before treatment, and at 3 and 12 months after treatment. RESULTS: From 3 to 18 months after surgery, paid labor resumption increased from 19 to 63 percent (P < 0.001). At 24 months after surgery, paid labor resumption was 61 percent. In a multivariate analysis, age older than 55 years (P <or= 0.001), lower education level (P <or= 0.003), shorter time since surgery (P < 0.001), preoperative radiotherapy (P = 0.02), lower valuation of overall health (P < 0.01), more physical symptom distress (P < 0.001), and more limitations in daily activities (P < 0.001) were all associated with less or later resumption of paid labor. The average amount of unpaid labor increased from 17.3 hours per week at 3 months to 21 hours per week at 12 months after surgery. In a multivariate analysis, only shorter time since surgery (P = 0.03) and male gender (P < 0.001) were related to less unpaid labor. CONCLUSIONS: Diagnosis and treatment of rectal cancer affect paid and unpaid labor. The impact on paid labor is most pronounced. Multiple other sociodemographic and quality of life-related variables also were associated with paid labor. Patient information and decision making on preoperative radiotherapy should include the effects on paid labor, and interventions focused on promoting paid labor participation in patients with rectal cancer should be tailored to the specific characteristics and needs of those patients.

Aged↗
PubMed2005

Self-reports of health-care utilization: diary or questionnaire?

OBJECTIVES: The feasibility and convergent validity of a cost diary and a cost questionnaire was investigated. METHODS: Data were obtained as part of a cost-utility analysis alongside a multicenter clinical trial in patients with resectable rectal cancer. A sample of 107 patients from 30 hospitals was asked to keep a weekly diary during the first 3 months after surgery, and a monthly diary from 3 to 12 months after surgery. A second sample of seventy-two patients from twenty-eight hospitals in the trial received a questionnaire at 3, 6, and 12 months after surgery, referring to the previous 3 or 6 months. Format and items of the questions were similar and included a wide range of medical and nonmedical items and costs after hospitalization for surgery. RESULTS: Small differences were found with respect to nonresponse (range, 79 to 86 percent) and missing questions (range, 1 to 6 percent between the diary and questionnaire). For most estimates of volumes of care and of costs, the diary and questionnaire did not differ significantly. Total 3-month nonhospital costs were 1,860 Euros, 1,280 Euros, and 1,050 Euros in the diary sample and 1,860 Euros, 1,090 Euros, and 840 Euros in the questionnaire sample at 3, 6, and 12 months after surgery, respectively (p = .50). However, with respect to open questions, the diary sample tended to report significantly more care. CONCLUSIONS: For the assessment of health-care utilization in economic evaluations alongside clinical trials, a cost questionnaire with structured closed questions may replace a cost diary for recall periods up to 6 months.

Colectomy↗
PubMed2005

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions.

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.

Adolescent↗
PubMed2005

Clinical relevance of occult tumor cells in lymph nodes from gastric cancer patients.

The current method for staging in gastric cancer is not sufficient as even after a complete primary tumor resection, patients with node-negative gastric cancer suffer from disease recurrence. In this study, the relation between disease recurrence and the presence of occult tumor cells (OTC) in lymph nodes from gastric cancer patients was evaluated. In a case-control design, lymph nodes from 40 cases (disease recurrence) and 41 controls (no disease recurrence and followed for at least five years) with gastric cancer were examined for the presence of OTC, that comprised micrometastases (MM; >0.2 mm and < or =2.0 mm) and isolated tumor cells (ITC; < or =0.2 mm). The original hematoxylin and eosin-stained sections of all lymph nodes from cases and controls were previously considered as tumor-negative by the local pathologist. Fresh hematoxylin and eosin-stained sections were screened by conventional microscopy. Histologic sections stained by immunohistochemistry with anticytokeratin antibodies CAM5.2 were screened by conventional and automated microscopy. Tumor cells were detected in lymph nodes from 40 of 81 (49%) patients. There was no significant difference in the presence of OTC, MM, or ITC between the case and control groups (P = 0.658, P = 0.691, P = 0.887, respectively). However, significantly more cases presented with 20% or more OTC-positive lymph nodes (P = 0.015). A multivariate logistic regression analysis showed that examination of less than five lymph nodes (odds ratio, 13.8; 95% confidence interval, 1.6-120.6, P = 0.018) was the only significant independent risk factor for disease recurrence, especially for locoregional disease recurrence (odds ratio, 20.4; 95% confidence interval, 2.2-190.8, P = 0.008). A similar analysis for distant disease recurrence showed a percentage of 20% or more OTC-positive lymph nodes to be the only significant independent risk factor (odds ratio, 15.6, 95% confidence interval, 1.6-151.4, P = 0.018). The sensitivity of immunohistochemistry evaluated by microscopy to identify cases with 20% or more OTC-positive lymph nodes increased from 8% for conventional microscopy to 22% for automated microscopy (McNemar's test, P = 0.063). The mere presence of OTC-positive lymph nodes in gastric cancer patients did not predict disease recurrence. However, the number of examined lymph nodes and the percentage of OTC-positive lymph nodes were independent risk factors for locoregional disease recurrence and distant disease recurrence, respectively. Automated microscopy was essential in identifying patients with 20% or more OTC-positive lymph nodes. Therefore, a maximum number of lymph nodes should be removed and meticulously examined for OTC to identify high-risk patients. These patients should be considered for additional treatment.

Aged↗
PubMed2005

Variability in densitometric assessment of pulmonary emphysema with computed tomography.

OBJECTIVES: The objectives of this study were to investigate whether computed tomography (CT) densitometry can be applied consistently in different centers; and to evaluate the reproducibility of densitometric quantification of emphysema by assessment of different sources of variation, ie, intersite, interscan and inter- and intraobserver variability, in comparison with intersubject variability. MATERIALS AND METHODS: In 5 different hospitals, 119 patients with emphysema were scanned using standardized protocols. In each site, an observer performed a quantitative densitometric analysis (including blood recalibration) on the corresponding patient group (n=23-25) and one observer analyzed the entire group of 119 patients. After several months, the latter observer analyzed all data for a second time. Subsequently, different sources of variation were assessed by variance component analysis with and without volume correction of the data. RESULTS: Inter- and intraobserver variability marginally contributes to the total variability (<0.001%). The interscan variability was 0.02% of the total variation after application of volume correction. The intersite variability was 48% as a result of one deviating CT scanner. Air recalibration normalized deviating air densities in CT scanners. Within sites, the intersubject variability ranged between 93% and 99% based on the analysis of 2 subsequent CT scans of the patients. CONCLUSIONS: Almost all variability in the density measurement of emphysema originates from differences between scanners and from differences in severity of emphysema between patients. Lung densitometry with multislice CT scanners is a highly reproducible measurement, especially if corrected for lung volume, because this reduces interscan variability.

Absorptiometry, Photon↗
PubMed2005

No effect of statin therapy on silent myocardial ischemia in patients with type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Coronary artery disease is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the prevalence of silent myocardial ischemia (SMI) and the effect of statin therapy on SMI in type 2 diabetic patients without manifest cardiovascular disease. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind trial was performed in 250 patients with type 2 diabetes without manifest cardiovascular disease. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, cerivastatin 0.4 mg was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change in ischemic episodes, duration, and burden as measured by 48-h ambulatory electrocardiography (AECG) over 2 years. RESULTS: At baseline, 47 of 233 (20%) evaluable ambulatory electrocardiograms showed evidence of ischemia. After 2 years, there was a trend toward more ischemia in both treatment groups, without significant differences between the changes in ischemic parameters (episodes P = 0.498; duration P = 0.697; burden P = 0.798) in the two treatment groups. Cardiovascular events occurred in 12 patients in the placebo group and in two patients in the statin group (P = 0.006). There was no relationship between these cardiovascular events and the presence of SMI at baseline. CONCLUSIONS: SMI occurred in 20% of type 2 diabetes patients without manifest cardiovascular disease. There was no effect from 2 years of statin therapy on SMI. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. AECG may not be a proper tool for risk stratification in patients with type 2 diabetes.

Awareness↗
PubMed2004

Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative trait loci influencing variation in human menopausal age.

Age at natural menopause may be used as parameter for evaluating the rate of ovarian aging. Environmental factors determine only a small part of the large variation in menopausal age. Studies have shown that genetic factors are likely to be involved in variation in menopausal age. To identify quantitative-trait loci for this trait, we performed a genomewide linkage study with age at natural menopause as a continuous quantitative phenotype in Dutch sister pairs, through use of a selective sampling scheme. A total of 165 families were ascertained using extreme selected sampling and were genotyped for 417 markers. Data were analyzed by Haseman-Elston regression and by an adjusted variance-components analysis. Subgroup analyses for early and late menopausal age were conducted by Haseman-Elston regression. In the adjusted variance-components analysis, 12 chromosomes had a LOD score of > or =1.0. Two chromosomal regions showed suggestive linkage: 9q21.3 (LOD score 2.6) and Xp21.3 (LOD score 3.1). Haseman-Elston regression showed rather similar locations of the peaks but yielded lower LOD scores. A permutation test to obtain empirical P values resulted in a significant peak on the X chromosome. To our knowledge, this is the first study to attempt to identify loci responsible for variability in menopausal age and in which several chromosomal regions were identified with suggestive and significant linkage. Although the finding of the region on the X chromosome comes as no surprise, because of its widespread involvement in premature ovarian failure, the definition of which particular gene is involved is of great interest. The region on chromosome 9 deserves further consideration. Both findings require independent confirmation.

Aging↗