Using a stepwise approach to simultaneously develop and validate machine learning based prediction models.

Accurate diagnosis of a disease is essential in healthcare. Prediction models, based on classical regression techniques, are widely used in clinical practice. Machine Learning (ML) techniques might be preferred in case of a large amount of data per patient and relatively limited numbers of subjects. However, this increases the risk of overfitting, and external validation is imperative. However, in the field of ML, new and more efficient techniques are developed rapidly, and if recruiting patients for a validation study is time consuming, the ML technique used to develop the first model might have been surpassed by more efficient ML techniques, rendering this original model no longer relevant. We demonstrate a stepwise design for simultaneous development and validation of prediction models based on ML techniques. The design enables - in one study - evaluation of the stability and robustness of a prediction model over increasing sample size as well as assessment of the stability of sensitivity/specificity at a chosen cut-off. This will shorten the time to introduction of a new test in health care. We finally describe how to use regular clinical parameters in conjunction with ML based predictions, to further enhance differentiation between subjects with and without a disease.

Differences in prevalence of hepatitis B virus infection and genotypes between ethnic populations in Suriname, South America.

Epidemiological data on hepatitis B virus (HBV) are needed to benchmark HBV elimination goals. We recently assessed prevalence of HBV infection and determinants in participants attending the Emergency Department in Paramaribo, Suriname, South America. Overall, 24.5% (95%CI = 22.7-26.4%) of participants had anti-Hepatitis B core antibodies, which was associated with older age (per year, adjusted Odds Ratio [aOR] = 1.03, 95%CI = 1.02-1.04), Afro-Surinamese (aOR = 1.84, 95%CI = 1.52-2.19) and Javanese ethnicity (aOR = 1.63, 95%CI = 1.28-2.07, compared to the grand mean). 3.2% of participants were Hepatitis B surface Ag-positive, which was also associated with older age (per year, aOR = 1.02, 95%CI = 1.00-1.04), Javanese (aOR = 4.3, 95%CI = 2.66-6.95) and Afro-Surinamese ethnicity (aOR = 2.36, 95%CI = 1.51-3.71). Sex, nosocomial or culturally-related HBV transmission risk-factors were not associated with infection. Phylogenetic analysis revealed strong ethnic clustering: Indonesian subgenotype HBV/B3 among Javanese and African subgenotypes HBV/A1, HBV/QS-A3 and HBV/E among Afro-Surinamese. Testing for HBV during adulthood should be considered for individuals living in Suriname, specifically with Javanese and Afro-Surinamese ancestry.

Multi-centre prospective study on diagnosing subtypes of lung cancer by exhaled-breath analysis.

OBJECTIVES: Lung cancer is a leading cause of mortality. Exhaled-breath analysis of volatile organic compounds (VOC's) might detect lung cancer early in the course of the disease, which may improve outcomes. Subtyping lung cancers could be helpful in further clinical decisions. MATERIALS AND METHODS: In a prospective, multi-centre study, using 10 electronic nose devices, 144 subjects diagnosed with NSCLC and 146 healthy subjects, including subjects considered negative for NSCLC after investigation, breathed into the Aeonose™ (The eNose Company, Zutphen, Netherlands). Also, analyses into subtypes of NSCLC, such as adenocarcinoma (AC) and squamous cell carcinoma (SCC), and analyses of patients with small cell lung cancer (SCLC) were performed. RESULTS: Choosing a cut-off point to predominantly rule out cancer resulted for NSCLC in a sensitivity of 94.4%, a specificity of 32.9%, a positive predictive value of 58.1%, a negative predictive value (NPV) of 85.7%, and an area under the curve (AUC) of 0.76. For AC sensitivity, PPV, NPV, and AUC were 81.5%, 56.4%, 79.5%, and 0.74, respectively, while for SCC these numbers were 80.8%, 45.7%, 93.0%, and 0.77, respectively. SCLC could be ruled out with a sensitivity of 88.9% and an NPV of 96.8% with an AUC of 0.86. CONCLUSION: Electronic nose technology with the Aeonose™ can play an important role in rapidly excluding lung cancer due to the high negative predictive value for various, but not all types of lung cancer. Patients showing positive breath tests should still be subjected to further diagnostic testing.

Impact of detection bias on the risk of gastrointestinal cancer and its subsites in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) may be a risk factor for gastrointestinal (GI) cancers, but variations in study designs of observational studies may have yielded biased results due to detection bias. Furthermore, differences in risk for GI cancer subsites have not been extensively evaluated. We aimed to determine the risk of GI cancer and its subsites in patients with T2DM and how it is affected by detection bias. METHODS: A matched cohort study was performed using the NCR-PHARMO database. New-users of ≥1 non-insulin anti-diabetic drug during 1998-2011 were matched with non-diabetic controls by year of birth, sex, and time between database entry and index. Cox regression analyses were performed with and without lag-period to estimate hazard ratios (HRs) for GI cancer and its subsites. Covariables included age, sex, use of other drugs and history of hospitalisation. RESULTS: An increased risk of GI cancer was observed in T2DM patients (HR 1.5, 95% confidence interval [CI] 1.3-1.7) compared with controls, which was attenuated in the 1-year lagged analysis (HR 1.4, 95% CI 1.2-1.7). Stratified by subsite, statistically significant increased risks of pancreatic (HR 4.7, 95% CI 3.1-7.2), extrahepatic bile duct (HR 4.2, 95% CI 1.5-11.8) and distal colon cancer (HR 1.5, 95% CI 1.1-2.1) were found, which remained statistically significantly increased in the lagged analysis. CONCLUSIONS: T2DM patients had a 40% increased risk of GI cancer. Increased GI cancer risks tended to be weaker when reducing detection bias by applying a 1-year lag-period. Future observational studies should therefore include sensitivity analyses in which this bias is minimised.

[Good clinical practice and the maintenance of ethical standards in medical research: advice for junior researchers working in mental health care]. / Good clinical practice en medisch-ethische toetsing: handvatten voor (beginnend) onderzoekers in de ggz.

BACKGROUND: In mental health care, more and more research is being done, particularly in the field of educational programmes. Unfortunately, junior researchers are often not fully informed about the rules and regulations relating to research and about medical ethics. Therefore, they are not in a position to make considered judgements that conform to good clinical practice and acceptable medical ethics.
AIM: To give practical advice to trainees, stimulating them to think carefully about ethical standards in patient-related research in mental health care. METHODS The article provides a practice-based overview of practical advice and ethical considerations.
RESULTS: We stress that before beginning their research, researchers should think very carefully about the ethics of medical research. Instructions and guidelines relating to medical and ethical standards are to be found in: directive for good clinical practice compiled by the central committee for human research (CCMO) with the accompanying e-learning module and in the basic course 'rules and organisation for clinical researchers' (BROK). Practical tips, illustrated with examples, provide a framework for stimulating thoughts on medical ethics. Finally, it is important to improve the ways in which research is embedded in the organisational structure of teaching programmes.
CONCLUSION: Basic information about GCP and the upholding of medical and ethical standards in patient-related research can be obtained from various sources. The main challenge is to ensure that GCP is firmly embedded in patient-related research undertaken by junior researchers.

Trill performance components vary with age, season, and motivation in the banded wren.

Acoustic displays with difficult-to-execute sounds are often subject to strong sexual selection, because performance levels are related to the sender's condition or genetic quality. Performance may also vary with age, breeding stage, and motivation related to social context. We focused on within-male variation in four components of trill performance in banded wren (Thryophilus pleurostictus) songs: note consistency, frequency bandwidth, note rate and vocal deviation. The latter is a composite measure reflecting deviation from the performance limit on simultaneously maximizing both frequency bandwidth and note rate. We compared the changes in these song parameters at three time scales: over the course of years, across the breeding season, and at different times of the day with contrasting agonistic contexts. Vocal deviation decreased and note consistency increased over years, suggesting that experience may improve individual proficiency at singing trills. Consistency also increased across the season, confirming that practice is important for this parameter. Although there was no significant seasonal change in vocal deviation, one of its components, note rate, increased during the season. Neither vocal deviation nor consistency varied with agonistic context. However, note rate increased during playback experiments simulating territorial intrusions compared to dawn chorus singing. The magnitude of a male's increase in note rate was positively correlated with his aggressive behavior during the playback experiment. Thus consistency, bandwidth, and vocal deviation indicate age, whereas trill rate flexibly indicates the singer's aggressive motivation. We also found evidence of a within-male trade-off between vocal deviation and consistency.

Leaky gut and diabetes mellitus: what is the link?

Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide, and a rapidly rising incidence, diabetes mellitus poses a great burden on healthcare systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dys-regulation of the intestinal barrier. Via alterations in the intestinal permeability, intestinal barrier function becomes compromised whereby access of infectious agents and dietary antigens to mucosal immune elements is facilitated, which may eventually lead to immune reactions with damage to pancreatic beta cells and can lead to increased cytokine production with consequent insulin resistance. Understanding the factors regulating the intestinal barrier function will provide important insight into the interactions between luminal antigens and immune response elements. This review analyses recent advances in the mechanistic understanding of the role of the intestinal epithelial barrier function in the development of type 1 and type 2 diabetes. Given our current knowledge, we may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of type 1 and type 2 diabetes.

Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study.

BACKGROUND: Microscopic colitis causes chronic watery diarrhoea. Recent studies have suggested an aetiological role for various medications, including proton pump inhibitors, in the pathogenesis of microscopic colitis. AIM: To determine whether an association exists between microscopic colitis and proton pump inhibitor use in patients with documented microscopic colitis vs. age- and gender-matched controls. METHODS: In this retrospective case-control study, cases of microscopic colitis from a secondary and tertiary referral medical centre diagnosed in the last 5 years were reviewed. Demographic characteristics, clinical, histological and endoscopic records, as well as exposure to PPIs and NSAIDs were assessed. Controls from the population were matched to cases by gender and by age. RESULTS: During the investigated period, 136 cases were identified in both hospitals. Of these, 95 cases of microscopic colitis were retrieved for detailed analysis. Exposure to proton pump inhibitors at the time of the histological diagnosis was significantly higher in patients with collagenous colitis than in controls [38% vs. 13%, P < 0.001; adjusted OR of 4.5 (95% CI 2.0-9.5)]. CONCLUSIONS: This observation confirms the presumed association between microscopic colitis and PPI use, and it supports the possible aetiological role of PPI exposure in the development of microscopic colitis.

Phenotype-genotype correlation in a familial IGF1R microdeletion case.

BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

Value judgements that matter to patients remain implicit in oncology guidelines: an observational study.

BACKGROUND: Clinical practice guidelines are often evidence-based. However, it is inevitable that there are value judgements in the practical recommendations contained in the guidelines. In order to see if patients are ultimately being supplied with sufficient information to help them make treatment decision, we determined 1) which value judgements influence the process of developing guidelines for palliative chemotherapy, and 2) whether these value judgements were made explicit in the final guideline report. METHODS: We studied the development process of six Dutch oncology guidelines in which palliative chemotherapy plays a substantial role. We observed the guideline development groups (GDGs), conducted semi-structured interviews with individual GDG members (including the chairs), and analysed the minutes of GDG meetings and subsequent versions of the guidelines. A value judgement was defined as a statement about the value of a patient outcome with regard to palliative chemotherapy. RESULTS: We identified the following value judgements in the process of guideline development: 1) consensus on what should be considered as valuable minimum patient outcomes, 2) preference for tailored treatment in situations where there is no evidence of treatment effect, 3) preference for 'doing something' even when there is sufficient evidence of no effect, and 4) the patient outcome of 'prolonging life'. These value judgements, however, were not reported in the final guideline. CONCLUSION: At least the last two value judgements mentioned are relevant for patients with incurable metastatic cancer in making decisions whether to undergo chemotherapy and what kind. Value judgements should be made explicit in guidelines, so that clinicians can transparently discuss treatment options with individual patients.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.

CONTEXT: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. OBJECTIVE: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. PATIENTS: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. INTERVENTION: Short prepubertal SGA children received GH 1mg/m(2)/day. OUTCOME MEASURES: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. RESULTS: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. CONCLUSION: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment.

CONTEXT: Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children. OBJECTIVES: To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function. PATIENTS: A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient. MEASUREMENTS: Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment. RESULTS: Baseline mean TSH was higher in preterm short SGA children than in age-matched controls (P < 0.05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment. CONCLUSION: Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.

Abdominal aortic aneurysms and thoracic aortic atheromas.

BACKGROUND: Abdominal aortic aneurysm (AAA) is associated with atherosclerosis elsewhere. Thoracic aortic atheromas (ATHs) seen on transesophageal echocardiography (TEE) are an important cause of stroke and peripheral embolization. The purposes of this study were to determine whether an association exists between AAA and ATHs and to assess the importance of screening patients with ATHs for AAA. METHODS: For the retrospective analysis, 109 patients with AAA and 109 matched controls were compared for the prevalence of ATHs on TEE and for historical variables. For the prospective analysis, screening for AAA on ultrasonography was performed in 364 patients at the time of TEE. RESULTS: Results of the retrospective analysis showed that ATHs were present in 52% of patients with AAA and in 25% of controls (odds ratio [OR] = 3.3; P =.00003). There was a significantly higher prevalence of hypertension, myocardial infarction, heart failure, smoking, and carotid or peripheral arterial disease in patients with AAA. However, only ATHs were independently associated with AAA on multivariate analysis (P =.001). Results of the prospective analysis showed that screening at the time of TEE in 364 patients revealed AAA in 13.9% of those with ATHs and in 1.4% of those without ATHs (P <.0001; OR = 11.4). CONCLUSIONS: (1) There is a strong, highly significant association between abdominal aneurysm and thoracic atheromas. (2) Patients with AAA may be at high risk for stroke because of the concomitance of thoracic aortic atheromas. (3) The high prevalence of abdominal aneurysm in patients with thoracic atheromas suggests that screening for abdominal aneurysm should be carried out in all patients with thoracic atheromas identified by TEE.

Unusual echocardiographic views of bicuspid and tricuspid pulmonic valves.

The pulmonary artery is typically seen on transthoracic echocardiography in its longitudinal axis. Therefore, short axis views of the pulmonic valve leaflets are not generally obtained, and the distinction between tricuspid and bicuspid pulmonic valves is difficult or impossible. Bicuspid pulmonic valve is one cause of pulmonic stenosis, which is especially common in tetralogy of Fallot. Presented here are 2 patients in whom the orientation of the pulmonary artery was unusual, and the pulmonic valve was seen en face. The first patient had tetralogy of Fallot and a bicuspid pulmonic valve. The severe obstruction to right ventricular outflow was infundibular. The second patient had severe stenosis of a tricuspid pulmonic valve, which was treated with balloon valvuloplasty. These unusual views of the pulmonic valve leaflets were obtained because of anterior displacement of the pulmonary artery, and precise anatomic delineation of the problem in each case was possible with transthoracic echocardiography.

Minimally invasive aortic valve replacement: echocardiographic and clinical results.

BACKGROUND: Port access has been described for mitral and bypass surgery. The purpose of this study was to review the clinical and echocardiographic outcomes of aortic valve replacement by use of port access. METHODS: Between 1996 and 1999, 153 port-access aortic valve replacements were performed at our institution. The mean age was 63 years (range 16-91 years); 58% were male. The New York Heart Association mean class was III; 18% were in class IV. Thirteen percent had diabetes, 42% hypertension, 7% prior transient ischemic episode or stroke, 7% lung disease, 3% renal failure, and 13% previous surgery. Echocardiograms were obtained after valve replacement in 125 patients (96 intraoperative transesophageal and 97 transthoracic echoes). RESULTS: Median length of stay was 8 days. There were no intraoperative deaths; 10 patients (6.5%) died in the postoperative period. Stroke occurred in 4 (2.6%), sepsis in 5 (3.3%), renal failure in 5 (3.3%), pneumonia in 3 (2%), and wound infection in 1 (0.7%). Tissue prosthesis was present in 83 and a mechanical prosthesis in 42. No or trace regurgitation was seen on 94 of 96 (98%) postbypass intraoperative echocardiograms and mild on 2. On follow-up echocardiograms, moderate regurgitation was seen in 4 of 97 (4.1%), mild-to-moderate in 2 (2.1%), mild in 18 (18.6%), and no or trace in 71 (73.2%). Of those who had aortic regurgitation on intraoperative or follow-up echocardiograms, it was paravalvular in 8. CONCLUSIONS: Minimally invasive aortic valve replacement with a port-access approach is feasible, even in high-risk patients. Small incisions, a low infection rate, and a short length of stay are attainable. However, the complications associated with traditional aortic valve replacement still occur. Echocardiography is valuable both for intraoperative monitoring and follow-up of this new procedure.

Acquired aorta-pulmonary artery fistula: diagnosis by multiple imaging modalities.

Acquired communication between the aorta and the pulmonary artery is a rare phenomenon. We describe two patients with a thoracic aortic aneurysm in whom the diagnosis of a communication with the pulmonary artery was first made on transthoracic echocardiography and then more completely elucidated by means of multiple imaging modalities: transesophageal echocardiography, epiaortic ultrasound, computed tomography, and magnetic resonance imaging. Representative images from these complementary studies are presented. A successful repair of the fistula was subsequently accomplished in both patients.

Thromboembolus from a ligated left atrial appendage.

The left atrial appendage of patients with mitral valve disease is commonly a source of thromboembolus and is often ligated during mitral valve surgery to diminish this risk. However, ligation is often incomplete. We describe a patient with a stroke whose only source of embolus was an incompletely ligated left atrial appendage. Attempts to exclude the left atrial appendage from the arterial circulation by suture ligation may not decrease the risk of thromboemboli and instead may increase such risk.

Hyperglycemic athymic nude mice: factors affecting in vitro insulin secretion.

The strain of athymic nude male mice (ANM) developed at the University of Southern California (USC) exhibits spontaneous hyperglycemia and relative hypoinsulinemia in vivo. To investigate factors that influence insulin secretion in this animal model of non-insulin-dependent diabetes mellitus, we utilized the isolated perfused mouse pancreas of the ANM-USC and control BALB/c mice. We compared in vitro glucose-induced insulin secretion in ANM-USC and control mice, inhibition of secretion by somatostatin, and variability of insulin secretion over the two-year period it took to complete these experiments. Glucose-induced insulin secretion from the isolated pancreas was biphasic in both ANM-USC and controls. Insulin secretion was quantitatively equal to or greater than control mice, depending on the phase of secretion analyzed and the source of the control mice. In contrast to pancreases of control mice, insulin secretion from ANM-USC pancreases was relatively resistant to inhibition of insulin secretion by somatostatin. Variability in insulin secretion over the two years in which these experiments were performed was greater from pancreases of control than that observed from pancreases of the ANM-USC. The hyperglycemic ANM-USC mouse does not demonstrate diminished insulin secretion in vitro yet is relatively hypoinsulinemic in vivo. Thus circulating factors other than somatostatin might contribute to the insulinopenic stage in this animal model.