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Biomedical subjects

J C van Houwelingen

Publications and source records attributed to J C van Houwelingen.

At least 19 recordsLinked to original sources
PubMed2006

Potential bias in Generalized Estimating Equations linkage methods under incomplete information.

The mean identity-by-descent (IBD) specification used in the Generalized Estimating Equations (GEE) methodology for linkage is only valid, strictly speaking, under the assumption of fully polymorphic markers. In practice, markers often provide only partial IBD information, which can potentially result in inconsistency of the locus location and gene effect estimates obtained by the GEE method. Using both simulations and theory, we identify some realistic conditions about marker information under which the validity of the GEE linkage methods may be arguable. Namely, researchers should not trust the GEE parameters' estimates and their associated confidence intervals in areas of the genome where IBD information is sparse or when this information changes abruptly. We show that properly standardized statistics based on IBD sharing provide a valid alternative.

Alleles↗
PubMed2005

Anxious-retarded depression: relation to two-year outcome of major depressive disorder.

BACKGROUND: Anxious-retarded depression is a two-dimensionally defined subcategory of depression derived from DSM-IV melancholia. It is related to increased plasma vasopressin, correlative plasma vasopressin and cortisol levels, and a positive family history. We now explored its relation with outcome. METHODS: Seventy depressed patients were included to follow-up for two years. Outcome was defined by time until full-remission. Cox regression analyses were used to compare anxious-retarded and non-anxious-retarded patients, as well as melancholic and non-melancholic patients. RESULTS: Anxious-retarded depression had poor outcome. LIMITATIONS: The number of patients was relatively small. CONCLUSION: The poor outcome of anxious-retarded depression further supports its validity.

Anxiety↗
PubMed2005

Long-term survival with non-proportional hazards: results from the Dutch Gastric Cancer Trial.

Randomized clinical trials with long-term survival data comparing two treatments often show Kaplan-Meier plots with crossing survival curves. Such behaviour implies a violation of the proportional hazards assumption for treatment. The Cox proportional hazards regression model with treatment as a fixed effect can therefore not be used to assess the influence of treatment of survival. In this paper we analyse long-term follow-up data from the Dutch Gastric Cancer Trial, a randomized study comparing limited (D1) lymph node dissection with extended (D2) lymph node dissection. We illustrate a number of ways of dealing with survival data that do not obey the proportional hazards assumption, each of which can be easily implemented in standard statistical packages.

Aged↗
PubMed2005

Studying the biological and technical sources of variation in telomere length of individual chromosomes.

BACKGROUND: Consistent average length differences between species and chromosome arm differences within species indicate that telomere length is genetically determined. This seems to contradict an observed large variation in lengths of the same human telomere between metaphases of the same individual. We examined the extent to which the variation in the telomeres of the human X and Y chromosomes is heritable, induced, or technical in origin. METHODS: Metaphase chromosomes were stained by fluorescence in situ hybridization with a telomere repeat-specific probe, and fluorescence intensities of the X and Y chromosomes were measured. If telomere length variation is predominantly genetically determined and a 50% probability of meiotic recombination between the pseudo-autosomal regions of Yp and Xp in the father is taken into account, one expects an equal chance that the Yp telomere of a son is derived from his father's Xp or Yp telomere. This implies that the Yp/Yq telomere ratios in fathers and sons will be identical in the absence of paternal meiotic recombination and different when recombination occurs. RESULTS: Among five father-son pairs, four showed similar Yp/Yq ratios (P > 0.05), whereas one pair exhibited a large difference in the Yp/Yq ratio that was attributable to a significantly longer Xp than Yp telomere in the father and a presumptive meiotic exchange between X and Y during paternal meiosis. Further, the Xq telomere exhibited a generally shorter telomere length than the others. CONCLUSIONS: The high variation in telomere length appeared to be intracellular (between sister chromatids) and, hence, technical in nature. We found no measurable induced variation in the cells studied, implying that, if induced variation exists, it is small compared with the technical variation.

Adult↗
PubMed2005

Score statistic to test for genetic correlation for proband-family design.

In genetic epidemiological studies informative families are often oversampled to increase the power of a study. For a proband-family design, where relatives of probands are sampled, we derive the score statistic to test for clustering of binary and quantitative traits within families due to genetic factors. The derived score statistic is robust to ascertainment scheme. We considered correlation due to unspecified genetic effects and/or due to sharing alleles identical by descent (IBD) at observed marker locations in a candidate region. A simulation study was carried out to study the distribution of the statistic under the null hypothesis in small data-sets. To illustrate the score statistic, data from 33 families with type 2 diabetes mellitus (DM2) were analyzed. In addition to the binary outcome DM2 we also analyzed the quantitative outcome, body mass index (BMI). For both traits familial aggregation was highly significant. For DM2, also including IBD sharing at marker D3S3681 as a cause of correlation gave an even more significant result, which suggests the presence of a trait gene linked to this marker. We conclude that for the proband-family design the score statistic is a powerful and robust tool for detecting clustering of outcomes.

Alleles↗
PubMed2005

Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.

BACKGROUND: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. METHODS: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. RESULTS: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. CONCLUSIONS: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.

Adult↗
PubMed2004

Sonographic assessment of non-malignant ovarian cysts: does sonohistology exist?

BACKGROUND: Transvaginal ultrasound (TVU) is feasible and accurate in the differentiation between non-malignant and malignant ovarian abnormalities. However, despite the clinical relevance, the accuracy of TVU in the differentiation between the many different non-malignant cysts is unknown. METHODS: Between 1992 and 2002, all women who had surgery at our centre because of a non-malignant ovarian cyst were included prospectively in this study. The sonographic characteristics as well as the expected histological diagnosis (the 'sonohistological diagnosis') were evaluated pre-operatively. This diagnosis was compared with the histopathological diagnosis, and diagnostic parameters [with 95% confidence interval (CI)] of the sonohistological diagnosis were calculated. Logistic models, with the sonographic characteristics as variables, were constructed for each histopathological diagnosis. RESULTS: A total of 406 women were included consecutively. The overall diagnostic accuracy of the sonohistological diagnosis was 60% (95% CI 0.56-0.65). Only in cases of simple ovarian cysts did the diagnostic accuracy of the respective logistic model exceed that of the sonohistological diagnosis (0.88 versus 0.81, P < 0.01). The diagnostic accuracy of the sonohistological diagnosis for endometriotic and dermoid ovarian cysts was significantly better compared with the respective logistic model (0.84 versus 0.71, P < 0.01 and 0.87 versus 0.82, P = 0.03, respectively). CONCLUSION: In approximately half of the non-malignant ovarian cysts, TVU is capable of distinguishing between the different histopathological diagnoses of non-malignant ovarian masses. Only in the diagnosis of simple ovarian cysts might use of the logistic models be helpful.

Adolescent↗
PubMed2004

Score test for detecting linkage to complex traits in selected samples.

We present a unified approach to selection and linkage analysis of selected samples, for both quantitative and dichotomous complex traits. It is based on the score test for the variance attributable to the trait locus and applies to general pedigrees. The method is equivalent to regressing excess IBD sharing on a function of the traits. It is shown that when population parameters for the trait are known, such inversion does not entail any loss of information. For dichotomous traits, pairs of pedigree members of different phenotypic nature (e.g., affected sib pairs and discordant sib pairs) can easily be combined as well as populations with different trait prevalences.

Analysis of Variance↗
PubMed2004

Risk estimation for healthy women from breast cancer families: new insights and new strategies.

Risk estimation in breast cancer families is often estimated by use of the Claus tables. We analyzed the family histories of 196 counselees; compared the Claus tables with the Claus, the BRCA1/2, the BRCA1/2/ models; and performed linear regression analysis to extend the Claus tables with characteristics of hereditary breast cancer. Finally, we compared the Claus extended method with the Claus, the BRCA1/2, and the BRCA1/2/u models. We found 47% agreement for Claus table versus Claus model; 39% agreement for Claus table versus BRCA1/2 model; 48% agreement for Claus table versus BRCA1/2/u model; 37% agreement for Claus extended method versus Claus model; 44% agreement for Claus extended model versus BRCA1/2 model; and 66% agreement for Claus extended method versus BRCA1/2/u model. The regression formula (Claus extended method) for the lifetime risk for breast cancer was 0.08 + 0.40 (*) Claus Table + 0.07 (*) ovarian cancer + 0.08 (*) bilateral breast cancer + 0.07 (*) multiple cases. This new method for risk estimation, which is an extension of the Claus tables, incorporates information on the presence of ovarian cancer, bilateral breast cancer, and whether there are more than two affected relatives with breast cancer. This extension might offer a good alternative for breast cancer risk estimation in clinical practice.

Breast Neoplasms↗
PubMed2004

Inhaled corticosteroids and growth of airway function in asthmatic children.

Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinally whether asthma affects growth of airway function relative to airspaces, and if so whether this is redressed by inhaled corticosteroids (ICS). Every 4 months for up to 3 yrs, lung function was assessed in 54 asthmatic children (initial age 7-16 yrs), who inhaled 0.2 mg salbutamol t.i.d. and 0.2 mg budesonide t.i.d. (beta2-agonist (BA)+ICS), or placebo (PL) t.i.d. (BA+PL) in a randomised, double-blind design. Measurements were carried out before and after maximal bronchodilation. Airway growth was assessed from the change of forced expiratory volume in one second and of maximal expiratory flows (at 60% and 40% of total lung capacity (TLC) remaining in the lung) relative to TLC, as measures of more central, intermediate and more peripheral airways. Growth patterns were compared with the longitudinal findings in 376 healthy children. Airway patency after maximal bronchodilation in patients on BA+PL remained reduced compared to healthy subjects, whereas in patients on BA+ICS a marked improvement was observed to subnormal. No differences between patients and controls could be demonstrated for growth patterns of central and intermediate airway function. Compliance with BA+ICS was 75% of the prescribed dose, resulting in significant, sustained improvement of symptoms and postbronchodilator calibre of central and intermediate airways to subnormal within 2 months, but postbronchodilator small airway patency remained reduced, though improved compared to patients on BA+PL. Anti-inflammatory treatment of asthmatic children is associated with normal functional development of central and intermediate airways. The persistently reduced postbronchodilator patency of peripheral airways may reflect remodelling, or insufficient anti-inflammatory treatment.

Administration, Inhalation↗
PubMed2003

Health-related quality of life in patients with systemic lupus erythematosus: development and validation of a lupus specific symptom checklist.

Reliable and sensitive measures are needed to evaluate the quality of life (QoL) in patients with systemic lupus erythematosus (SLE). No lupus specific questionnaires are available. This study describes the development and validation of a disease-specific questionnaire for lupus patients, which assesses the presence and burden of 38 disease- and treatment-related symptoms: the SLE Symptom Checklist (SSC). Reliability and reproducibility were tested in respectively 87 and 28 stable SLE patients. The internal consistency (Cronbach's alpha coefficients 0.89) and test-retest reliability (Pearson product-moment correlation coefficient between 0.67 and 0.87) were satisfactory. Concurrent validity was supported by significant, but moderate correlations with other measures of subjective well-being and functional status. Responsiveness was measured in 17 patients with lupus nephritis treated with cyclophosphamide, at start of therapy and 1 year thereafter. A significant change in number of symptoms and total distress level was found. It is concluded that the SSC has satisfactory psychometric properties and appears suitable for both clinical and research purposes.

Female↗
PubMed2003

The value of transvaginal ultrasound to monitor the position of an intrauterine device after insertion. A technology assessment study.

BACKGROUND: The intrauterine device (IUD) is an effective contraceptive method. The contraceptive power as well as the side-effects of IUD are thought to relate to the position of the IUD in the uterine cavity. We assessed the accuracy of clinical evaluation of IUD position. METHODS: A prospective comparative study was performed. The clinical evaluation was compared with the TVU measurement of IUD position both immediately after insertion and 6 weeks after insertion. The primary outcome measures were the positive and negative predictive values (PPV and NPV) of the clinical evaluation of IUD position. RESULTS: 195 women were included consecutively, 181 women (92.8%) were available for follow-up. The PPV and NPV of clinical evaluation of IUD position immediately after insertion were respectively 0.60 (95% CI: 0.39-0.81) and 0.98 (95% CI: 0.96-1.0). The prevalence of an abnormally positioned IUD was 7.7% (95% CI: 3.9-11.4). The PPV and NPV of the clinical evaluation at follow-up were respectively 0.54 (95% CI: 0.26-0.81) and 1.0 (95% CI: 0.98-1.0). The prevalence of abnormal position was 4.0% (95% CI: 1.7-7.1). CONCLUSION: Clinical evaluation is an excellent test for the evaluation of the position of an IUD and routine TVU is not indicated for this purpose.

Adolescent↗
PubMed2002

Score test for detecting linkage to quantitative traits.

The two most popular methods to detect linkage of a quantitative trait to a marker are the Haseman-Elston regression method and the variance components likelihood-ratio test. In the literature, these methods are frequently compared and the relative advantages and disadvantages of each method are well known. In this article, we derive a score test for the variance component attributable to a specific quantitative trait locus and show that for sib-pairs it is mathematically equivalent to a recently proposed version of the Haseman-Elston method that optimally combines the sum squared and the difference squared of the centered phenotype values of the sibs. Because score tests and likelihood-ratio tetsts are equivalent for large sample sizes, the variance components likelihood-ratio test is also asymptotically equivalent to this optimal Haseman-Elston test. This fact gives a theoretical explanation of the empirical observation from simulation studies reporting similar power of the variance components likelihood-ratio test and the optimal Haseman-Elston method. Perhaps more importantly for practical purposes, the score test can also be extended in a natural way to support the simultaneous analysis of more than two subjects and multivariate phenotypes.

Chromosome Mapping↗
PubMed2001

Cytokine and IL-12 receptor mRNA discriminate between different clinical subtypes in multiple sclerosis.

Little is known about the involvement of cytokines in the pathogenesis of primary progressive (PP) multiple sclerosis (MS). We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF-alpha, IFN-gamma, IL-10, IL-4, TGF-beta, IL-12Rbeta1, and IL-12Rbeta2 mRNA expression in unstimulated white blood cells showed significant differences between relapsing-remitting (RR), secondary progressive (SP) and PP MS patients, and healthy controls. All clinical subtypes showed unique mRNA expression patterns as compared to the controls. Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-beta mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels. Both in PP and SP patients, IFN-gamma and IL-10 mRNA were decreased compared to RR patients and controls. PP patients were unique in that they showed decreased IL-12Rbeta1 mRNA. In conclusion, our data show that the assessment of cytokine (receptor) mRNA profiles is useful to discriminate between the different clinical subtypes and suggest that different cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.

Adult↗
PubMed2001

Impact of Huntington's disease on quality of life.

The purpose of this study was to systematically assess the impact of Huntington's disease (HD) on patients' health-related quality of life (QOL). Seventy-seven patients with a clinically confirmed diagnosis of HD were interviewed by means of the Sickness Impact Profile (SIP). Additional data were gathered on patients' motor performance by means of the motor section of the Unified Huntington Disease Rating Scale (UHDRS), and cognitive performance by means of the Mini-Mental State (MMS). Patients had high scores on the SIP subscales, indicating moderate to severe functional impairment. Total Motor Score (TMS), MMS scores, and the duration of HD were significantly correlated with patients' scores on the SIP, and predicted a significant amount of variance of the Physical Dimension of the SIP, but not of the Psychosocial Dimension. We conclude that HD has a great impact on patients' physical and psychosocial well-being, the latter being more severely affected. Implications for further research and clinical practice are discussed.

Adaptation, Psychological↗
PubMed2000

Contrasting responses to interferon beta-1b treatment in relapsing-remitting multiple sclerosis: does baseline interleukin-12p35 messenger RNA predict the efficacy of treatment?

Interferon (IFN)-beta treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18, tumor necrosis factor-alpha (TNFalpha), IFNgamma, IL-10, IL-4, or transforming growth factor-beta in unstimulated whole blood of 26 RR-MS patients changed during 6 months of IFNbeta-1b treatment. In these patients, a significant change was found in TNFalpha mRNA, whereas changes in IL-12 receptor-beta2 and IL-10 mRNA showed a trend. IFNbeta-1b-related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR-MS patients classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNbeta-1b treatment with respect to IL-10, TNFalpha, and IL-18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFalpha and IL-18 mRNA as well as a transient increase in IL-10 mRNA. Baseline levels of IL-12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patients under investigation.

Adult↗