Nested Case Control Design Research Articles

Parental psychopathology and offspring attention-deficit/hyperactivity disorder in a nationwide sample

ObjectiveTo study the associations between a wide range of parental psychiatric disorders and offspring attention-deficit/hyperactivity disorder (ADHD). MethodThis study is based on a nested case–control design. The association between parental registered psychiatric diagnoses and offspring ADHD was examined adjusting for socioeconomic and prenatal factors. Data was linked from Finnish nationwide registers. The cases (n = 10,409) were all the children born between years 1991 and 2005 in Finland and diagnosed with ADHD by the end of 2011. Four controls without ADHD (n = 39,124) were matched for every case by sex, age and place of birth. Main outcomes were adjusted odds ratio (aOR) for parental diagnosis of cases vs controls. Analyses were further stratified by sex. Disorders diagnosed before and after birth were analyzed separately. ResultsThe odds ratio for ADHD increased when only mother (aOR 2.2, 95% CI 2.0–2.3), only father (aOR 1.7, 95% CI 1.6–1.8) and both parents (aOR 3.6, 95% CI 3.3–4.0) were diagnosed. Maternal diagnosis showed stronger association than paternal. The weight of association between several parental disorders and offspring ADHD were similar. Maternal psychopathology overall showed stronger associations with girls than boys with ADHD. The diagnoses registered after birth did not show stronger association than the diagnoses registered before. Conclusions: Maternal psychopathology showing stronger association than paternal implies that environmental factors or their interaction with genetic factors partly mediates the risk of parental psychopathology. Similar associations between several maternal psychiatric disorders and offspring ADHD points towards the need for investigating some common mother-related risk factors.

IMPROVING EFFICIENCY IN BIOMARKER INCREMENTAL VALUE EVALUATION UNDER TWO-PHASE DESIGNS.

Cost-effective yet efficient designs are critical to the success of biomarker evaluation research. Two-phase sampling designs, under which expensive markers are only measured on a subsample of cases and non-cases within a prospective cohort, are useful in novel biomarker studies for preserving study samples and minimizing cost of biomarker assaying. Statistical methods for quantifying the predictiveness of biomarkers under two-phase studies have been proposed (Cai and Zheng, 2012; Liu, Cai and Zheng, 2012). These methods are based on a class of inverse probability weighted (IPW) estimators where weights are 'true' sampling weights that simply reflect the sampling strategy of the study. While simple to implement, existing IPW estimators are limited by lack of practicality and efficiency. In this manuscript, we investigate a variety of two-phase design options and provide statistical approaches aimed at improving the efficiency of simple IPW estimators by incorporating auxiliary information available for the entire cohort. We consider accuracy summary estimators that accommodate auxiliary information in the context of evaluating the incremental values of novel biomarkers over existing prediction tools. In addition, we evaluate the relative efficiency of a variety of sampling and estimation options under two-phase studies, shedding light on issues pertaining to both the design and analysis of biomarker validation studies. We apply our methods to the evaluation of a novel biomarker for liver cancer risk conducted with a two-phase nested case control design (Lok et al., 2010).

Neonatal septic arthritis: Clinical profile and predictors of outcome

Background: Neonatal septic arthritis deserves a special attention due to its subtle signs and symptoms and catastrophic consequences. There is paucity of literature regarding the clinical profile and predictors of outcome in neonatal septic arthritis. Objectives: The objective was to study the clinical profile of neonates admitted with septic arthritis, their clinical and radiological outcomes on follow-up, and factors that predict outcomes. Methodology: Neonates with septic arthritis as assessed by retrospective case sheet review were included. Prospective data collection of clinical and radiological outcomes was done during follow-upvisits. Children with good outcomes (controls) were compared to those with poor outcomes (cases) subsequently to identify the predictors of outcomes using a nested case–control design. Results: Data of 70 neonates admitted with septic arthritis were collected. Single joint involvement was common (75.8%), and hip joint was the most common joint involved. Gram-negative organisms were predominant (72%), and Klebsiella was the most common organism isolated from joint aspirate (36%), followed by Escherichia coli and Staphylococcus aureus. Of 52 babies who turned for follow-up, half had poor outcomes. In univariate analysis,multiple joint involvement (odds ratio [OR] 4.79, [confidence interval (CI): 1.14-20.21]), pre-intervention period ?7 days (OR 92, [CI: 14.06-601.9]), culture positive joint aspirate (OR 3.70, [CI: 1.55-11.86]), and restricted range of joint movements at discharge (OR 83.3, [CI: 9.2-749.9]) were significantly associated with poor outcomes. Pre-intervention period ?7 days (adjusted OR 107.99, [CI: 5.16-2258.8]) and restricted joint mobility at discharge (adjusted OR 139.53, [CI: 9.03-2154.04]) were the independent predictors of poor overall outcome by logistic regression analysis. Conclusions: Long pre-intervention period and restricted joint mobility at discharge were independent predictors of poor outcome in neonatal septic arthritis. We emphasize the importance ofearly diagnosis, prompt referral to tertiary centers, timely surgical intervention, appropriate measures to ensure good joint mobility, and regular follow-up in these neonates to achieve best outcomes.

Prediction of early response to steroids in nephrotic syndrome patients aged between 2 and 10 years

ObjectiveThe primary objective was to predict onset of remission within 10 days of starting corticosteroid treatment in nephrotic syndrome patients aged between 2 and 10 years (either first episode or first relapse) using clinical and laboratory variables. The secondary objective was to compare changes in CD4 count and percentage among newly diagnosed cases. MethodProspective cohort study with a nested case–control design was conducted from September 2009 to August 2010 after institutional ethical clearance. Included were cases aged 2–10 years diagnosed as nephrotic syndrome based on standard clinical and laboratory criteria. Controls were age- and sex-matched healthy subjects recruited from the outpatient's department. ResultsIncluded were 44 cases (26 newly diagnosed and 16 were first relapse) cases of nephrotic syndrome and 38 healthy age- and sex-matched controls. Variables in the linear regression model predicting remission were sex, presence of tuberculosis, Low-Density Lipoprotein (LDL)/High Density Lipoprotein (HDL) ratio and antihypertensive medication, serum LDL, serum triglyceride, and serum creatinine. CD4 count, CD4%, and CD4% rise were significantly high in first episode of nephrotic syndrome as compared to controls. Serum Very Low Density Lipoprotein (VLDL) was raised in late responders of first episode of nephrotic syndrome. ConclusionFemale gender, concomitant tuberculosis, and raised serum VLDL delayed onset of remission while use of angiotensin converting enzyme inhibitors in hypertensive patients decreased the duration of proteinuria in cases of nephrotic syndrome in children.

Prevalence and associated factors of congenital anomalies in a tertiary care centre in Tamilnadu

Background: A birth defect or congenital anomaly is an abnormality of structure, function or body metabolism that is present at birth and results in physical or mental disability. Evaluation and management of newborns with one or more malformations present a significant challenge to the healthcare providers and families. Despite major advances in understanding the etiology and pathogenesis, malformations remain a leading cause of infant mortality. This study brings about the prevalence of congenital anomalies among antenatal patients delivering beyond the period of viability, 22 weeks in a tertiary care centre in Tamilnadu and also the pattern of anomalies, along with the associated factors. Materials and Methods: A cross sectional study with nested case control design was conducted in a tertiary care centre in Taminadu for one year from July 2015 to June 2016. Those fetuses induced in second trimester following detection by ultrasound and those babies detected to have congenital anomalies by postnatal examination were included in the study. Data of 191 cases and 191 controls were collected by interviewing the mothers and reviewing the existing patient records. Relevant antenatal, natal, postnatal and past illnesses were recorded in a proforma and analysed. Results: In the study period, 191 babies out of 9877 were anomalous with a prevalence of 1.93%. Anomalies of the central nervous system were the commonest (35.6%). The ultrasound detection rate was 67.01%. Maternal age >25 years was seen in 55%. About 15.7% of the mothers had consanguineous marriage. The distribution among primigravida and multipara are almost similar.16.2% of cases had a history of infertility in the mother. 8.4% of the cases had a family history. About 4.7% cases had a history of exposure to antiepileptic drugs. Maternal diabetes mellitus and epilepsy contributed 32.5% and 4.5% of cases respectively. Intrauterine growth restriction and amniotic fluid abnormalities were commonly associated. Conclusion: The study helps to know the pattern of congenital anomalies and the relationship of various gestational and familial factors and the importance of ultrasound in diagnosing anomalies. Surveillance of anomalies should be a must and all maternity hospitals should have their own anomaly register. Parents of any surviving anomalous child should receive emotional support and reassurance.

Breaking the matching in nested case–control data offered several advantages for risk estimation

ObjectiveTo demonstrate the advantage of using weighted Cox regression to analyze nested case–control data in overcoming limitations encountered with traditional conditional logistic regression. Study Design and SettingWe analyzed data from 1,051 women who were sampled in a case–control study of lung cancer nested within a cohort of breast cancer patients. We investigated how lung cancer risk is associated with radiation therapy and modified by smoking, with both conditional logistic regression and weighted Cox regression models. ResultsIn contrast to logistic regression, weighted Cox regression exploited the information regarding radiation dose received by each individual lung. The weighted method also mitigated a problem of overmatching apparent in the data and revealed that the risk of radiotherapy-associated lung cancer was modified by smoking (P = 0.026) with a hazard ratio of 4.09 (2.31, 7.24) in unexposed smokers and 8.63 (5.04, 14.79) in smokers receiving doses >13 Gy. The cumulative risk of lung cancer increased steadily with increasing radiotherapy dose in smokers, whereas no such effect was found in nonsmokers. ConclusionThe weighted Cox regression makes optimal and versatile use of the information in a nested case–control design, allowing dose–response analysis of exposure to paired organs and enabling the estimation of cumulative risk.

Altered growth trajectory of head circumference during infancy and schizophrenia in a National Birth Cohort

Identification of abnormalities in the developmental trajectory during infancy of future schizophrenia cases offers the potential to reveal pathogenic mechanisms of this disorder. Previous studies of head circumference in pre-schizophrenia were limited to measures at birth. The use of growth acceleration of head circumference (defined as the rate of change in head circumference) provides a more informative representation of the maturational landscape of this measure compared to studies based on static head circumference measures. To date, however, no study has examined whether HC growth acceleration differs between pre-schizophrenia cases and controls. In the present study, we employed a nested case control design of a national birth cohort in Finland. Cases with schizophrenia or schizoaffective disorder (N=375) and controls (N=375) drawn from the birth cohort were matched 1:1 on date of birth (within 1month), sex, and residence in Finland at case diagnosis. Longitudinal data were obtained on head circumference from birth through age 1. Data were analyzed using a new nonparametric Bayesian inversion method which allows for a detailed understanding of growth dynamics. Adjusting for growth velocity of height and weight, and gestational age, there was significantly accelerated growth of head circumference in females with schizophrenia from birth to 2months; the findings remained significant following Bonferroni correction (p<0.0125). This is the first study to report abnormal HC growth acceleration, a more sensitive measure of somatic developmental deviation of this measure, in schizophrenia.

Inpatient Suicide in a Psychiatric Hospital: A Nested Case-control Study.

Objective:Risk factors for inpatient suicide are different from those in the general population. We examined sociodemographic and clinical variables of patients who committed suicide as an inpatient in a psychiatric hospital in India.Methods:Matched retrospective nested case–control design was adopted. Ten patients who died by suicide as inpatients between 2000 and 2013 were included, along with fifty controls, matched with respect to age, sex, diagnosis, and period of admission.Results:Suicide completers were mostly unskilled in occupation (P = 0.03), had a history of past suicide attempts (P < 0.001), shorter duration of hospital stay (P = 0.001), poorer improvement on psychopathology (P = 0.02), and were having more suicidal ideation (P = 0.02). Significantly more completers were receiving antidepressants (P = 0.04).Conclusion:This study adds to the existing sparse literature on inpatient suicides from Asia. Strength of the study was close matching between case and controls and blindedness. Limitations were retrospective design, and variations in prescription behavior and treatment decisions.

Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score

Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m3. Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (−8, 97%) per 10μg/m3 exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia.

Natural experiments and large databases in respiratory and cardiovascular disease.

A number of scientific questions cannot be tested in a laboratory, clinic or clinical trial setting. In many cases, observational data can be used to test such hypotheses.This article illustrates how epidemiology can contribute and shows the different ways of using observational data through three approaches: 1) prospective cohort study design; 2) time series analysis; and 3) a nested case-control design in pharmacoepidemiology.In a prospective cohort study design, three cohorts were merged to study lung function decline, testing the importance of different trajectories of lung function decline for developing chronic obstructive pulmonary disease (COPD). Using these three well-described cohorts it was documented that maximally attained lung function in early adulthood is as important as excess decline in forced expiratory volume in 1 s for the development of COPD. Time series analysis is used to examine exposures and disease over time. In a recent review of cardiovascular disease some interesting associations, and not least lack of associations, were presented. Assessing effects of drugs in database studies is challenging. In a nested case-control design in a large cohort study, statins were found to reduce the risk of COPD exacerbations. These findings will be discussed.Observational data from large databases, as well as carefully collected data in cohort studies, can be used to test hypotheses that may not be addressed in a traditional experimental setting.

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls

BackgroundFolate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. ObjectiveTo investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. Design, setting, and participantsA study was performed with a nested case–control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. Outcome measurements and statistical analysisIncident PCa and subtype by stage and grade. Results and limitationsHigher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02–1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01–1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28–4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. ConclusionsThe association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. Patient summaryFolate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Has deinstitutionalization affected inpatient suicide? Psychiatric inpatient suicide rates between 1990 and 2013 in Israel

ObjectiveTo examine variations in rates of inpatient suicide and clinical risk factors for this phenomenon. MethodThe National Israeli Psychiatric Hospitalization Case Registry was used to study inpatient suicide. Clinical risk factors for inpatient suicide were examined in a nested case control design. ResultsBetween 1990 and 2013 there were 326 inpatient suicides, at an average of one inpatient suicide per 1614 admissions. A significant decline in rates of suicide per admission over time (p<0.001) was associated with a reduced number of beds (p<0.001) and a decline in nationwide suicide rates (p=0.001). Clinical risk factors for inpatient suicide were: affective disorders (OR=5.95), schizoaffective disorder (OR=5.27), schizophrenia (OR=3.82), previous suicide attempts (OR=2.59), involuntary hospitalization (OR=1.67), and more previous hospitalizations (OR=1.16,). A multivariate model with sensitivity of 27.3% and specificity of 95.3% for inpatient suicide, showed a positive predictive value of 0.4%. ConclusionsThe absolute number and rates of inpatient suicide per admission have decreased over time, probably due to the decreased number of beds lowering total time at risk. Patients with affective and psychotic disorders and with previous suicide attempts have the greatest risk of inpatient suicide. However, clinical characteristics do not enable identification of patients who are at risk for suicide.

Evaluation of the Accuracy of T-SPOT.TB for the Diagnosis of Ocular Tuberculosis in a BCG-vaccinated, Non-endemic Population

ABSTRACTPurpose: To determine the performance of T-SPOT.TB, an interferon gamma release assay test, in patients with ocular tuberculosis (TB) in a BCG-vaccinated, non-endemic population.Methods: We employed a nested case–control design. In total, 45 subjects were enrolled (23 patients with ocular tuberculosis and 22 patients with other causes of uveitis). A blood sample was collected from each subject, and T-SPOT.TB was executed. Laboratory professionals were blinded to the disease status of each subject.Results: Five patients were excluded because of indeterminate results. The calculated sensitivity and specificity were 0.80 and 0.85, respectively. The positive likelihood ratio was 5.33 and the negative likelihood ratio was 0.23. The overall accuracy of the test was 0.83.Conclusions: T-SPOT.TB adequately diagnosed ocular TB. This technique is particularly useful in populations where BCG vaccinations are still mandatory.

Using the entire history in the analysis of nested case cohort samples

Countermatching designs can provide more efficient estimates than simple matching or case-cohort designs in certain situations such as when good surrogate variables for an exposure of interest are available. We extend pseudolikelihood estimation for the Cox model under countermatching designs to models where time-varying covariates are considered. We also implement pseudolikelihood with calibrated weights to improve efficiency in nested case-control designs in the presence of time-varying variables. A simulation study is carried out, which considers four different scenarios including a binary time-dependent variable, a continuous time-dependent variable, and the case including interactions in each. Simulation results show that pseudolikelihood with calibrated weights under countermatching offers large gains in efficiency if compared to case-cohort. Pseudolikelihood with calibrated weights yielded more efficient estimators than pseudolikelihood estimators. Additionally, estimators were more efficient under countermatching than under case-cohort for the situations considered. The methods are illustrated using the Colorado Plateau uranium miners cohort. Furthermore, we present a general method to generate survival times with time-varying covariates. Copyright © 2016 John Wiley & Sons, Ltd.

H-type hypertension and risk of stroke in chinese adults: A prospective, nested case-control study.

ObjectivesTo investigate the independent and joint associations of hyperhomocysteinemia and hypertension with incident stroke and stroke death in Chinese adults.MethodsAbout 39,165 rural Chinese adults aged 35 years or older who had no history of stroke at the baseline study were prospectively followed to determine major cardiovascular events, with an average follow-up of 6.2 years. Using a nested case–control design, this report includes 179 incident stroke cases (121 stroke deaths) and 179 controls without vascular events from the original cohort matched by age, sex, community, and length of plasma storage. Baseline plasma total homocysteine (tHcy) measurements were obtained for all subjects. Logistic regression analysis was performed to investigate the independent and joint associations between H-type hypertension, defined as subjects with concomitant hypertension and elevated homocysteine (≥10 μmol/L), and risk of incident stroke and stroke death, after adjusting for important covariates.ResultsWe analyzed each risk factor independently and jointly. For analysis, homocysteine was divided into three groups: low (tHcy <10 μmol/L), moderate (≥10 μmol/L tHcy <20 μmol/L), and high (tHcy≥20μmol/L). Compared to subjects in the low group, the odds ratios (95% CI) of incident stroke for those in the moderate group and the high group were 1.7 (0.8–3.7) and 3.1 (1.2–8.6), respectively. The odds ratios (95% CI) of stroke death for the moderate and high groups were 2.8 (1.1–7.4) and 5.1 (1.6–16.4), respectively. Hypertension was also independently associated with a higher risk of incident stroke and stroke death: 3.8 (2.3–6.4) and 3.2 (1.8–6.0), respectively, compared to those without hypertension. When analyzed jointly, the highest risk was found among patients with H-type hypertensive with both hyperhomocysteinemia and hypertension: 12.7 (2.8–58.0) for incident stroke and 11.7 (2.5–54.7) for stroke death.ConclusionsThis study provides strong evidence that hyperhomocysteinemia and hypertension are two independent, modifiable risk factors, which act additively to increase the risk of incident stroke and stroke death. The results strongly suggest that H-type hypertension is a major risk factor for vascular disease and mortality, and those with H-type hypertension may particularly benefit from homocysteine-lowering therapy along with anti-hypertension therapy in Chinese populations.

Prediction of Sjögren's Syndrome Years Before Diagnosis and Identification of Patients With Early Onset and Severe Disease Course by Autoantibody Profiling

ObjectiveAutoantibodies are highly characteristic of primary Sjögren's syndrome (SS) and represent important tools for studying its pathogenesis. Nonetheless, thus far, no systematic investigations have assessed the presence of autoantibodies before diagnosis. This study was undertaken to analyze how early and in what order autoantibodies appear, how predictive they are of primary SS, and whether they identify disease subsets.MethodsA nested case–control design linking data from the Malmö primary SS registry and 3 Swedish healthcare biobanks was applied. In all, 175 serum samples obtained from 117 individuals before diagnosis of primary SS and 1 serum sample from each of 117 matched controls were analyzed for antinuclear antibodies (ANAs), rheumatoid factor (RF), and antibodies against Ro 60/SSA, Ro 52/SSA, and La/SSB.ResultsConsidering all patients with primary SS who were autoantibody positive after diagnosis, at least one autoantibody specificity was detected in 81% up to 20 years (median 4.3–5.1 years) before diagnosis. Those found most often were ANAs, followed by RF, anti–Ro 60/SSA, anti–Ro 52/SSA, and anti‐La/SSB. Anti‐Ro/SSA and anti‐La/SSB antibodies were strongly associated with the risk of developing primary SS, especially early‐onset disease and a severe disease course. When Bayesian prior prevalence estimates for primary SS were included in the calculation, prediagnostic anti–Ro 60/SSA and anti–Ro 52/SSA had the highest positive predictive values (25% and 100%, respectively).ConclusionOur findings indicate that autoantibodies are present for up to 18–20 years before the diagnosis of primary SS, but we cannot exclude even earlier seropositivity, since for most patients, the earliest sample analyzed was positive. In families with multiple cases of autoimmune disease, autoantibody profiling, along with assessment of genetic risk, enables identification of susceptible individuals in a predisease state.

Mitochondrial DNA Copy Number in Peripheral Blood Cells and Risk of Developing Breast Cancer.

Increased mitochondrial DNA (mtDNA) copy number in peripheral blood cells (PBC) has been associated with the risk of developing several tumor types. Here we evaluate sources of variation of this biomarker and its association with breast cancer risk in a prospective cohort study. mtDNA copy number was measured using quantitative real-time PCR on PBC DNA samples from participants in the UK-based Breakthrough Generations Study. Temporal and assay variation was evaluated in a serial study of 91 women, with two blood samples collected approximately 6-years apart. Then, associations with breast cancer risk factors and risk were evaluated in 1,108 cases and 1,099 controls using a nested case-control design. In the serial study, mtDNA copy number showed low assay variation but large temporal variation [assay intraclass correlation coefficient (ICC), 79.3%-87.9%; temporal ICC, 38.3%). Higher mtDNA copy number was significantly associated with younger age at blood collection, being premenopausal, having an older age at menopause, and never taking HRT, both in cases and controls. Based on measurements in a single blood sample taken on average 6 years before diagnosis, higher mtDNA copy number was associated with increased breast cancer risk [OR (95% CI) for highest versus lowest quartile, 1.37 (1.02-1.83); P trend = 0.007]. In conclusion, mtDNA copy number is associated with breast cancer risk and represents a promising biomarker for risk assessment. The relatively large temporal variation should be taken into account in future analyses.

Altered glutathione system is associated with the presence of distal symmetric peripheral polyneuropathy in type 2 diabetic subjects

Distal symmetric peripheral polyneuropathy (DSPN) is a highly prevalent complication of diabetes. However, underlying pathophysiological mechanisms are multiple and not well understood. The aim of our study was to analyze the oxidative stress levels in circulating mononuclear cells by measuring the glutathione system, malondialdehyde and oxidized-LDL, in 60 type 2 diabetic patients from a well-characterized cohort of 196 type 2 diabetic patients. Using a nested case–control design, we studied 30 type 2 diabetic patients with distal symmetric polyneuropathy and 30 diabetic controls without this complication, according to the Neuropathy Disability Score. We have found that diabetic patients with distal symmetric polyneuropathy showed significantly lower values of reduced glutathione (GSH) and reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. These data indicate an increased consumption of glutathione in mononuclear cells from patients with distal symmetric polyneuropathy. No significant differences were found in malondialdehyde or in oxidized-LDL levels comparing both groups. These data show an altered glutathione response in circulating monocytes from diabetic patients with distal symmetric polyneuropathy.

Prodromal symptoms in knee osteoarthritis: a nested case–control study using data from the Osteoarthritis Initiative

SummaryObjectiveIn order to gain a better understanding of the timing of emergent symptoms of osteoarthritis, we sought to investigate the existence, duration and nature of a prodromal symptomatic phase preceding incident radiographic knee osteoarthritis (ROA).DesignData were from the incidence cohort of the Osteoarthritis Initiative (OAI) public use datasets. Imposing a nested case–control design, ten control knees were selected for each case of incident tibiofemoral ROA between 2004 and 2010 from participants aged 45–79 years. Candidate prodromal symptoms were Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) subscale scores and individual items, available up to 4 years prior to the time of incident ROA. Multi-level models were used to estimate the length of the prodromal phases.ResultsThe prodromal phase for subscale scores ranged from 29 months (KOOS Other Symptoms) to 37 months (WOMAC Pain). Pain and difficulty on activities associated with higher dynamic knee loading were associated with longer prodromal phases (e.g., pain on twisting/pivoting (39 months, 95% confidence interval: 13, 64) vs pain on standing (25 months: 7, 42)).ConclusionsOur analysis found that incident ROA is preceded by prodromal symptoms lasting at least 2–3 years. This has potential implications for understanding phasic development and progression of osteoarthritis and for early recognition and management.

The Quasi-cohort approach in pharmacoepidemiology: upgrading the nested case-control.

Observational studies of drug effects conducted using health care mega-databases often involve large cohorts with multiple time-varying exposures and covariates. These present formidable technical challenges in data analysis, necessitating sampling approaches such as nested case-control designs. The nested case-control approach is, however, baffling to medical journal readers, particularly the comparisons involving "cases" versus "controls" and the convoluted way in which forward-looking relations from exposure to outcome are extracted from backward-looking data. I propose a "quasi-cohort" approach involving alternative ways of data presentation and analysis that are more in line with the underlying cohort design, including the computation of quasi-rates, rate ratios, and quasi-rate differences. I illustrate the quasi-cohort approach using data from a study of pneumonia risk associated with inhaled corticosteroid use in a cohort of 163,514 patients with chronic obstructive pulmonary disease, including 20,344 who had the outcome event of pneumonia hospitalization during more than 304 million person-days of follow-up.