What makes a biostatistician?

Biostatisticians play an important role in medical research. They are co-responsible for an appropriate and efficient study design, they are involved in monitoring the study conduct, they plan and perform the data analysis, and they are involved in interpreting and publishing the results. However, how are the biostatisticians prepared for their tasks and responsibilities? Graduate programs in biostatistics are being offered, but some practicing biostatisticians completed their studies in a mathematical or epidemiological program, or obtained their degree in subject-specific fields (such as medicine or biology). Therefore, the expertise and the competencies can vary widely between the individual biostatisticians, also depending on the application field. In this article, focusing on European and US practices, we discuss the required professional expertise for the main areas of applications in the medical field as well as the necessary soft skill competencies of a biostatistician.     

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

A nationally representative survey of hospital malnutrition: the Italian PIMAI (Project: Iatrogenic MAlnutrition in Italy) study

Aim and methods  Nutrition, unhealthy lifestyles and cancer appear to be strictly related, but few authors have analysed the interest in dietary information of cancer patients and their families. This survey was conducted in the Veneto area (Italy) to investigate the concern of cancer patients and their family members about diet as a health tool before and after diagnosis of cancer. Results  Seven hundred and four questionnaires were collected: 380 from cancer patients and 324 from family members of cancer subjects. Breast cancer (BC) was the most frequent disease for patients (61.8%) as well as families (26.5%). Generally, the importance of having precise diet information after diagnosis is recognised by 40.3% of patients, with significant differences between the various types of cancer: gastric and colon/rectum cancer (GCC) patients were more concerned than BC women about precise information concerning a diet to follow immediately after diagnosis (p = 0.000, ODs = 3.10, CI 1.68–5.71) or during treatments (p = 0.001, ODs = 2.67, CI 1.46–4.89). The nutritional information is supplied to patients in 34% of cases and to relatives in 30.3%, often from non-medical sources. In total healthcare workers (family doctor, oncologist, surgeon, dietician) represented the exclusive source of dietary information for 24.9% of patients and 22.9% of family members. Diet after diagnosis changes in 69.1% of GCC patients and in 39.2% of BC women. Relatives, particularly women, report difficulties preparing patients’ meals in 30.7% of cases, changes in the eating habits of the entire family in 29.9% and discontent connected with patients diet in 13.9%. The concern about proper nutrition after diagnosis increases more in GCC subjects (p < 0.025) when compared to BC subjects and in patients with more recent diagnosis (p < 0.041) when compared with patients with diagnosis >5 years ago, while in family members the interest in diet after diagnosis increases more in women than in men (p < 0.030) without other differences regarding the degree of relationship, type of cancer or diagnosis time. Relatives (92.7%) have more interest in nutritional education than patients (74.9%). Cancer patients <65 years were more interested in educational initiatives concerning nutrition (p = 0.000, ODs = 4.46, CI 2.6–7.4) than older patients (>65 years) and female subjects were more concerned than male patients (p = 0.008, ODs = 2.11, CI 1.2–3.6). Conclusions  The interest in the dietary knowledge and in educational initiatives concerning nutrition is high in cancer patients and their relatives, although it decreases with the age. The poor attention paid to nutrition of cancer patients by various healthcare workers deserves consideration, since the psychophysical wellbeing and perhaps also survival of cancer patients can be improved by correct dietary management, as well as, naturally, by the principal treatments themselves.     

Angiostatin overexpression in Morris hepatoma results in decreased tumor growth but increased perfusion and vascularization.

Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. METHODS: To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, H2 15O and 68Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. RESULTS: Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being cocultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. CONCLUSION: hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transduction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET.     

Co-operative mineralization and protein self-assembly in amelogenesis: silica mineralization and assembly of recombinant amelogenins in vitro

An amorphous silica mineralization technique was used to produce inorganic/protein composites to elucidate the structure and mechanism of formation of amelogenin assemblies, which may play an important role in regulating enamel structure during the initial stages of amelogenesis. Full-length recombinant amelogenins from mouse (rM179) and pig (rP172) were investigated along with key degradation products (rM166 and native P148) lacking the hydrophilic C terminus found in parent molecules. The resulting products were examined using transmission electron microscopy and/or small-angle X-ray scattering. Using protein concentrations of 0.1–3 mg ml⁻¹, large monodisperse spheres of remarkably similar mean diameters were observed using rM179 (124 ± 4 nm) and rP172 (126 ± 7 nm). These spheres also exhibited 'internal structure', comprising nearly spherical monodisperse particles of ≈ 20 nm in diameter. In the presence of rM166, P148, and bovine serum albumin (control), large unstructured and randomly shaped particles (250–1000 nm) were observed. Without added protein, large dense spherical particles of silica (mean ≈ 500 nm) lacking internal structure were produced. These findings demonstrate that full-length amelogenins have the ability to form higher-order structures, whereas amelogenins that lack the hydrophilic C terminus do not. The results also suggest that full-length amelogenin can guide the formation of organized mineralized structures through co-operative interactions between assembling protein and forming mineral.     

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.     

Dermoscopic Evolution of a Congenital Combined Nevus in Childhood

Background. A combined nevus most commonly consists of a blue nevus in combination with a Clark or Spitz nevus. Dermoscopically, combined nevus can mimic melanoma owing to the presence of dermoscopic features common to both types of lesions. Benign clinical and dermoscopic changes can occur in nevi over time, especially in children and young adults.
Objective. To describe the dermoscopic evolution of a congenital combined nevus showing unusual dermoscopic features.
Methods. Digital dermoscopic analysis was performed at the initial visit and after 8 months. The lesion was surgically excised and histopathologically examined.
Results. An asymptomatic plaque with a central blue area and peripheral brown pigmentation located on the back of a 13-year-old boy was diagnosed dermoscopically as combined nevus. Dermoscopic analysis 8 months later showed color changes from steel blue to gray-blue and black in the central area of the lesion, an increased number of blue-black dots or globules, and peripheral irregular streaks. Histopathology revealed typical features of a congenital combined nevus (blue nevus + compound nevus).
Conclusion. Over time, congenital combined nevus may show clinical and dermoscopic changes in size, color, and structure. Surgical excision is recommended when clinical and dermoscopic features are equivocal and the diagnosis of melanoma cannot be ruled out.
ANGELA FERRARI, MD, GIAN PIERO LOZZI, MD, MARIA CONCETTA FARGNOLI, MD, AND KETTY PERIS, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.     

Awake one stage bilateral thoracoscopic sympathectomy for palmar hyperhidrosis: a safe outpatient procedure.

OBJECTIVE: To verify the feasibility and compare the results of thoracoscopic sympathectomy under local anaesthesia (LA) and spontaneous breathing vs. general anaesthesia (GA) with one-lung ventilation. METHODS: Two groups of consecutive patients underwent one stage bilateral T2-T3 thoracoscopic sympathectomy under LA (n=15) and GA (n=30) by the same surgical team for treatment of primary palmar hyperhidrosis. The groups were homogeneous for relevant demographic, physiological and clinical data, including pulmonary function. In both groups, patient's satisfaction was evaluated 24h after surgery by a simple interview and scored into five grades (1=very poor to 5=excellent), while quality of life (QOL) was evaluated by SF-36 and Nottingham's Health Profile questionnaires before and 6 months after surgery. A cost comparison between groups concerning devices, drugs, global in operating room time, medical personnel and hospital stay was also carried out. RESULTS: No operative mortality was recorded. The overall in operating room time for the whole bilateral procedure under LA was 63.55+/-10.58 vs. 86.05+/-5.75 under GA (P<0.01) and temperature increased in all patients from a baseline of 25.42+/-0.56 up to 32.15+/-0.84 degrees C. All patients undergone LA were discharged the same day after a chest roentgenogram and a short stay in the outpatient clinic. Among them three patients (20%) experienced a minimal (<30%) pneumothorax that required no treatment, while five (33.3%) had a trunk compensatory sweating that spontaneously resolved on the long run. Patients undergoing GA were discharged after a mean stay of 1.38+/-0.6 days. Among these, eight (26.6%) had prolonged trunk compensatory sweating that did not persist longer than 3 months. At a follow-up of 7.16+/-2.97 months, QOL was significantly improved with no difference between groups. The overall rate of satisfaction was greater in the LA group (P<0.05). CONCLUSIONS: In our study, awake one stage bilateral thoracoscopic sympathectomy for palmar hyperhidrosis could be safely and effectively performed as an outpatient procedure in patients refusing GA. Postoperative quality of life was equal to that in patients undergone the same procedure under GA, while patient satisfaction was better and cost were significantly reduced.     

Effects of tracheal extubation on coronary blood flow,myocardial metabolism and systemic haemodynamic responses

Global coronary blood flow and metabolism were measured in seven patients on the first postoperative day following coronary revascularization to test the hypothesis that tracheal extubation produces adverse haemodynamic responses akin to those observed during tracheal intubation. Regional coronary flow and metabolic measurements were made in five of the seven patients. Extubation from a continuous positive airway pressure (CPAP) of 5 cm H₂O was associated with a statistically significant rise in cardiac index from 3.44 ± 0.23 L · min^-1 · m^-2 to 3.73 ± 0.15L·min^-1 ·m^-2 related to an increase in stroke index, without significant changes in heart rate, mean arterial and pulmonary capillary wedge pressure. Consequently the changes in myocardial oxygen consumption (8.52 ± 0.55 to 8.85 ± 0.93 ml · min^-1) and coronary blood flow (172 ± 18 to 179 ± 17 ml·min^-1) were less prominent than those reported during intubation, where substantial rises in myocardial oxygen consumption and coronary flow occurred. Two patients experienced cardiac lactate production but there were no changes in systemic or coronary haemodynamics, nor were there clinical or electrocardiographic signs of ischaemia. We conclude that extubation does not appear to be associated with adverse systemic or coronary haemodynamic responses in patients following coronary bypass grafting. However, the revascularized myocardium may remain vulnerable to anaerobic metabolism in the immediate postoperative period. Pour savoir si comme ľintubation, ľextubation de la trachée provoque des perturbations hémodynamiques, on a mesuré le métabolisme et la circulation coronarienne globale chez sept patients, au lendemain ďun pontage aorto-coronarien. On a aussi calculé les valeurs régionales de ces mêmes variables pour cinq ďentre eux. Ľindex cardiaque de 3.44 ± 0.23 L · min^-1 · m^-2 sous pression positive en respiration spontanée (CPAP) de 5 cm. H₂O s’est élevé à 3.73 ± 0.15 L · min^-1 · m^-2 post-extubation avec une augmentation significative du volume ďéjection. La fréquence cardiaque et les pressions artérielles moyennes et capillaires pulmonaires n’ont pas changé. Ainsi ľaugmentation de la consommation ďoxygène du myocarde de 8.52 ± 0.55 à 8.85 ± 0.93 ml · min^-1 et celle du flot coronarien de 172 ± 18 à 179 ± 17 ml · min^-1 ont été moindres que celles, importantes, déjà observées lors de ľintubation. On a noté chez deux patients une production de lactate par le myocarde, sans changement de ľhémodynamic systémique et coronarienne non plus que de signe clinique ou électrocardiographique ďischémie. Donc, après un pontage coronarien, ľextubation ne semble pas causer ďeffet néfaste sur les circulations systémique et coronarienne, toutefois, le myocarde revascularisé peut demeurer sensible au métabolisme anaérobique.     

The micronutrient content of traditional Greek foods

In the context of the EURRECA project (EURopean micronutrient RECommendations Aligned), we have estimated the micronutrient content of traditional Greek foods in relation to international recommendations. Many of these foods showed a rich micronutrient profile and a file was developed listing a total of 137 traditional Greek foods and dishes. This work indicates that in order to meet micronutrient requirements, a simple solution would be to adhere to traditional dietary patterns, at least for the Mediterranean populations, and reinstate traditional foods into the daily diet.