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1.  Modeling the impact of hepatitis C viral clearance on end-stage liver disease in an HIV co-infected cohort with Targeted Maximum Likelihood Estimation 
Biometrics  2013;70(1):144-152.
Summary
Despite modern effective HIV treatment, hepatitis C virus (HCV) co-infection is associated with a high risk of progression to end-stage liver disease (ESLD) which has emerged as the primary cause of death in this population. Clinical interest lies in determining the impact of clearance of HCV on risk for ESLD. In this case study, we examine whether HCV clearance affects risk of ESLD using data from the multicenter Canadian Co-infection Cohort Study. Complications in this survival analysis arise from the time-dependent nature of the data, the presence of baseline confounders, loss to follow-up, and confounders that change over time, all of which can obscure the causal effect of interest. Additional challenges included non-censoring variable missingness and event sparsity.
In order to efficiently estimate the ESLD-free survival probabilities under a specific history of HCV clearance, we demonstrate the doubly-robust and semiparametric efficient method of Targeted Maximum Likelihood Estimation (TMLE). Marginal structural models (MSM) can be used to model the effect of viral clearance (expressed as a hazard ratio) on ESLD-free survival and we demonstrate a way to estimate the parameters of a logistic model for the hazard function with TMLE. We show the theoretical derivation of the efficient influence curves for the parameters of two different MSMs and how they can be used to produce variance approximations for parameter estimates. Finally, the data analysis evaluating the impact of HCV on ESLD was undertaken using multiple imputations to account for the non-monotone missing data.
doi:10.1111/biom.12105
PMCID: PMC3954273  PMID: 24571372
Double-robust; Inverse probability of treatment weighting; Kaplan-Meier; Longitudinal data; Marginal structural model; Survival analysis; Targeted maximum likelihood estimation
2.  Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril 
Purpose
Angiotensin-converting enzyme (ACE) inhibitors are recommended for patients with chronic kidney disease (CKD) because they slow disease progression. But physicians’ concerns about the risk of hyperkalemia (elevated serum potassium level), a potentially fatal adverse effect, may limit optimal management with ACE-inhibitors. We synthesized known predictors of hyperkalemia into a prognostic risk score to predict the risk of hyperkalemia.
Methods
We assembled a retrospective cohort of adult patients with possible CKD (at least one estimated glomerular filtration rate (eGFR) value less than 60 mL/min/1.73m2) who started an ACE-inhibitor (i.e., incident users) between 1998 and 2006 at a health maintenance organization. We followed patients for hyperkalemia: (1) potassium value > 5.5 mmol/L; or, (2) diagnosis code for hyperkalemia. Cox regression synthesized a priori predictors recorded in the electronic medical record into a risk score.
Results
We followed 5,171 patients and 145 experienced hyperkalemia, a 90-day risk of 2.8%. Predictors included: age, eGFR, diabetes, heart failure, potassium supplements, potassium-sparing diuretics, and a high dose for the ACE-inhibitor (lisinopril). The risk score separated high-risk patients (top quintile, observed risk of 6.9%) from low-risk patients (bottom quintile, observed risk of 0.7%). Predicted and observed risks agreed within 1% for each quintile. The risk increased gradually in relation to declining eGFR with no apparent threshold for contraindicating ACE-inhibitors.
Conclusions
The risk score separated high-risk patients (who may need more intensive laboratory monitoring) from low-risk patients. The risk score should be validated in other populations before it is ready for use in clinical practice.
doi:10.1002/pds.1923
PMCID: PMC3905673  PMID: 20112435
hyperkalemia; chronic kidney disease; ACE-inhibitors; risk score; cohort study; adverse effects
3.  LONG-TERM BEHAVIORAL CONSEQUENCES OF INFANT FEEDING 
SUMMARY
Observational (nonexperimental) studies of the association of infant feeding and subsequent child or adult behavior are prone to residual confounding by subtle differences in psychological attributes and interactional styles of mothers who breastfeed vs those who formula-feed. We followed up 13,889 6.5-year-old Belarusian children who participated in a large cluster-randomized trial of a breastfeeding promotion intervention. Behavior was evaluated using the Strengths and Difficulties Questionnaire (SDQ), completed independently by the children’s parents and teachers. We compared the results of experimental (intention-to-treat, ITT) and observational analyses (based on feeding actually received), both adjusted for clustering. Observational analyses were additionally adjusted for geographic region and urban vs rural residence; child sex, age at follow-up, and birth weight; and maternal and paternal education. No differences between the randomized experimental vs control groups were observed in ITT analyses. In contrast, small but statistically significant associations with weaning prior to 3 months were observed for parent and teacher SDQ scores on total difficulties, conduct problems, and hyperactivity, even after multivariate adjustment. The absence of associations based on ITT analyses, in contrast with the significant associations based on observed BF duration, strongly suggests that the latter are biased by residual confounding.
doi:10.1111/j.1365-3016.2011.01211.x
PMCID: PMC3763822  PMID: 21980939
4.  A simulation study of finite-sample properties of marginal structural Cox proportional hazards models 
Statistics in medicine  2012;31(19):2098-2109.
Summary
Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a) unadjusted, (b) regression-adjusted, (c) unstabilized and (d) stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE) and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and ten study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased while crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared to other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on large-sample theory and provided accurate estimates of the hazard ratio.
doi:10.1002/sim.5317
PMCID: PMC3641777  PMID: 22492660
Bias; Causal inference; Marginal structural models; Monte Carlo study
5.  Smoking cessation attempts among adolescent smokers: a systematic review of prevalence studies 
Tobacco Control  2007;16(6):e8.
Objective
To synthesise estimates of the prevalence of cessation attempts among adolescent smokers generally, and according to age and level of cigarette consumption.
Data sources
PubMed, ERIC, and PsychInfo databases and Internet searches of central data collection agencies.
Study selection
National population‐based studies published in English between 1990 and 2005 reporting the prevalence, frequency and/or duration of cessation attempts among smokers aged ⩾10 to <20 years.
Data extraction
Five reviewers determined inclusion criteria for full‐text reports. One reviewer extracted data on the design, population characteristics and results from the reports.
Data synthesis
In total, 52 studies conformed to the inclusion criteria. The marked heterogeneity that characterised the study populations and survey questions precluded a meta‐analysis. Among adolescent current smokers, the median 6‐month, 12‐month and lifetime cessation attempt prevalence was 58% (range: 22–73%), 68% (range 43–92%) and 71% (range 28–84%), respectively. More than half had made multiple attempts. Among smokers who had attempted cessation, the median prevalence of relapse was 34, 56, 89 and 92% within 1 week, 1 month, 6 months, and 1 year, respectively, following the longest attempt. Younger (age<16 years) and non‐daily smokers experienced a similar or higher prevalence of cessation attempts compared with older (age ⩾16 years) or daily smokers. Moreover, the prevalence of relapse by 6 months following the longest cessation attempt was similar across age and smoking frequency.
Conclusions
The high prevalence of cessation attempts and relapse among adolescent smokers extends to young adolescents and non‐daily smokers. Cessation surveillance, research and program development should be more inclusive of these subgroups.
doi:10.1136/tc.2006.018853
PMCID: PMC2807205  PMID: 18048598
6.  Time-modified Confounding 
American Journal of Epidemiology  2009;170(6):687-694.
According to the authors, time-modified confounding occurs when the causal relation between a time-fixed or time-varying confounder and the treatment or outcome changes over time. A key difference between previously described time-varying confounding and the proposed time-modified confounding is that, in the former, the values of the confounding variable change over time while, in the latter, the effects of the confounder change over time. Using marginal structural models, the authors propose an approach to account for time-modified confounding when the relation between the confounder and treatment is modified over time. An illustrative example and simulation show that, when time-modified confounding is present, a marginal structural model with inverse probability-of-treatment weights specified to account for time-modified confounding remains approximately unbiased with appropriate confidence limit coverage, while models that do not account for time-modified confounding are biased. Correct specification of the treatment model, including accounting for potential variation over time in confounding, is an important assumption of marginal structural models. When the effect of confounders on either the treatment or outcome changes over time, time-modified confounding should be considered.
doi:10.1093/aje/kwp175
PMCID: PMC2800260  PMID: 19675141
bias (epidemiology); confounding factors (epidemiology); structural model
7.  CNODES: the Canadian Network for Observational Drug Effect Studies 
Open Medicine  2012;6(4):e134-e140.
Abstract
Although administrative health care databases have long been used to evaluate adverse drug effects, responses to drug safety signals have been slow and uncoordinated. We describe the establishment of the Canadian Network for Observational Drug Effect Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network (DSEN). CNODES is a distributed network of investigators and linked databases in British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia. Principles of operation are as follows: (1) research questions are prioritized by the coordinating office of DSEN; (2) the linked data stay within the provinces; (3) for each question, a study team formulates a detailed protocol enabling consistent analyses in each province; (4) analyses are “blind” to results obtained elsewhere; (5) protocol deviations are permitted for technical reasons only; (6) analyses using multivariable methods are lodged centrally with a methods team, which is responsible for combining the results to provide a summary estimate of effect. These procedures are designed to achieve high internal validity of risk estimates and to eliminate the possibility of selective reporting of analyses or outcomes. The value of a coordinated multi-provincial approach is illustrated by projects studying acute renal injury with high-potency statins, community-acquired pneumonia with proton pump inhibitors, and hyperglycemic emergencies with antipsychotic drugs. CNODES is an academically based distributed network of Canadian researchers and data centres with a commitment to rapid and sophisticated analysis of emerging drug safety signals in study populations totalling over 40 million.
PMCID: PMC3654509  PMID: 23687528
8.  Modeling Fetal Weight for Gestational Age: A Comparison of a Flexible Multi-level Spline-based Model with Other Approaches 
We present a model for longitudinal measures of fetal weight as a function of gestational age. We use a linear mixed model, with a Box-Cox transformation of fetal weight values, and restricted cubic splines, in order to flexibly but parsimoniously model median fetal weight. We systematically compare our model to other proposed approaches. All proposed methods are shown to yield similar median estimates, as evidenced by overlapping pointwise confidence bands, except after 40 completed weeks, where our method seems to produce estimates more consistent with observed data. Sex-based stratification affects the estimates of the random effects variance-covariance structure, without significantly changing sex-specific fitted median values. We illustrate the benefits of including sex-gestational age interaction terms in the model over stratification. The comparison leads to the conclusion that the selection of a model for fetal weight for gestational age can be based on the specific goals and configuration of a given study without affecting the precision or value of median estimates for most gestational ages of interest.
doi:10.2202/1557-4679.1305
PMCID: PMC3173606  PMID: 21931571
multi-level models; fetal growth; small for gestational age
9.  Should Gestational Weight Gain Recommendations be Tailored by Maternal Characteristics? 
American Journal of Epidemiology  2011;174(2):136-146.
The authors tested whether the relation between gestational weight gain (GWG) and 5 adverse pregnancy outcomes (small-for-gestational-age (SGA) birth, large-for-gestational-age (LGA) birth, spontaneous preterm birth, indicated preterm birth, and unplanned cesarean delivery) differed according to maternal race/ethnicity, smoking, parity, age, and/or height. They also evaluated whether GWG guidelines should be modified for special populations by studying GWG and risk of at least 1 adverse outcome within different subgroups. Data came from a cohort of 23,362 normal-weight mothers who delivered singletons at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003–2008). Adequacy of GWG was defined as observed GWG divided by recommended GWG. The synergy analysis found that the combination of smoking, black race/ethnicity, primiparity, or short height with poor GWG was associated with an excess risk of SGA birth, while high GWG combined with each of these characteristics diminished risk of LGA birth in comparison with the same GWG among the women's counterparts. Nevertheless, there were no significant or meaningful differences in the risk of at least 1 adverse outcome between the GWG recommended by the Institute of Medicine in 2009 and the GWG that minimized risk of the composite outcome. These findings do not support the tailoring of GWG guidelines on the basis of a mother's smoking status, race/ethnicity, parity, age, or height among normal-weight women.
doi:10.1093/aje/kwr064
PMCID: PMC3167680  PMID: 21633118
ethnic groups; gestational age; parity; practice guidelines as topic; pregnancy; smoking; weight gain
10.  Breastfeeding and Infant Size: Evidence of Reverse Causality 
American Journal of Epidemiology  2011;173(9):978-983.
Infants who receive prolonged and exclusive breastfeeding grow more slowly during the first year of life than those who do not. However, infant feeding and growth are dynamic processes in which feeding may affect growth, and prior growth and size may also influence subsequent feeding decisions. The authors carried out an observational analysis of 17,046 Belarusian infants who were recruited between June 1996 and December 1997 and who participated in a cluster-randomized trial of a breastfeeding promotion intervention. To assess the effects of infant size on subsequent feeding, the authors restricted the analysis to infants breastfed (or exclusively breastfed) at the beginning of each follow-up interval and examined associations between weight or length at the beginning of the interval and weaning or discontinuation of exclusive breastfeeding by the end of the interval. Smaller size (especially weight for age) was strongly and statistically significantly associated with increased risks of subsequent weaning and of discontinuing exclusive breastfeeding (adjusted odds ratios = 1.2–1.6), especially between 2 and 6 months, even after adjusment for potential confounding factors and clustered measurement. The authors speculate that similar dynamic processes involving infant crying, other signs of hunger, and supplementation/weaning undermine causal inferences about the “effect” of prolonged and exclusive breastfeeding on slower infant growth.
doi:10.1093/aje/kwq495
PMCID: PMC3390166  PMID: 21430194
body size; breast feeding; causal inference; evidence; infant
11.  Predicting Poor Outcomes in Heart Failure 
The Permanente Journal  2011;15(4):4-11.
Background: Health plans must prioritize disease management efforts to reduce hospitalization and mortality rates in heart failure patients.
Methods and Results: We developed a risk model to predict the 5-year risk of mortality or hospitalization for heart failure among patients at a large health maintenance organization. We identified 4696 patients who had an echocardiogram and a heart failure diagnosis from 1999 to 2004.
We observed a 56% five-year risk of hospitalization for heart failure or death (95% confidence interval, 54% to 58%). The hazard ratios for echocardiogram data contributed statistically significantly to the model, but echocardiogram findings did not improve our ability to predict risk accurately once we had accounted for demographic characteristics and clinical findings. A more complex model demonstrated a modest capacity to accurately predict risk. Our risk model discriminated the highest- and lowest-risk patients with limited success–the observed risk was 3 times higher in the highest risk quintile, compared with the lowest-risk quintile.
Conclusions: Using data available from electronic health records, we developed a series of risk-prediction models for poor outcomes in patients with heart failure. We found that a relatively simple model is as effective as a more complex model, but that all the models predict with only modest accuracy. Until better prediction variables are available for heart failure patients, our prediction model may be valuable for prioritizing centralized disease management program efforts by stratifying patients according to their absolute risk of poor outcomes.
PMCID: PMC3267558  PMID: 22319410
12.  Illustrating bias due to conditioning on a collider 
That conditioning on a common effect of exposure and outcome may cause selection, or collider-stratification, bias is not intuitive. We provide two hypothetical examples to convey concepts underlying bias due to conditioning on a collider. In the first example, fever is a common effect of influenza and consumption of a tainted egg-salad sandwich. In the second example, case-status is a common effect of a genotype and an environmental factor. In both examples, conditioning on the common effect imparts an association between two otherwise independent variables; we call this selection bias.
doi:10.1093/ije/dyp334
PMCID: PMC2846442  PMID: 19926667
Bias; selection; methods; epidemiologic
13.  Variation in Child Cognitive Ability by Week of Gestation Among Healthy Term Births 
American Journal of Epidemiology  2010;171(4):399-406.
The authors investigated variations in cognitive ability by gestational age among 13,824 children at age 6.5 years who were born at term with normal weight, using data from a prospective cohort recruited in 1996–1997 in Belarus. The mean differences in the Wechsler Abbreviated Scales of Intelligence were examined by gestational age in completed weeks and by fetal growth after controlling for maternal and family characteristics. Compared with the score for those born at 39–41 weeks, the full-scale intelligence quotient (IQ) score was 1.7 points (95% confidence interval (CI): −2.7, −0.7) lower in children born at 37 weeks and 0.4 points (95% CI: −1.1, 0.02) lower at 38 weeks after controlling for confounders. There was also a graded relation in postterm children: a 0.5-points (95% CI: −2.6, 1.6) lower score at 42 weeks and 6.0 points (95% CI: −15.1, 3.1) lower at 43 weeks. Compared with children born large for gestational age (>90th percentile), children born small for gestational age (<10th percentile) had the lowest IQ, followed by those at the 10th–50th percentile and those at the >50th–90th percentile. These findings suggest that, even among healthy children born at term, cognitive ability at age 6.5 years is lower in those born at 37 or 38 weeks and those with suboptimal fetal growth.
doi:10.1093/aje/kwp413
PMCID: PMC3435092  PMID: 20080810
birth weight; cognition; gestational age; term birth
14.  HIV and HCV discordant injecting partners and their association to drug equipment sharing 
Our objective was to examine the association between HIV and HCV discordant infection status and the sharing of drug equipment by injection drug users (IDUs). IDUs were recruited from syringe exchange and methadone treatment programmes in Montreal, Canada. Characteristics of participants and their injecting partners were elicited using a structured questionnaire. Among 159 participants and 245 injecting partners, sharing of syringes and drug preparation equipment did not differ between concordant or discordant partners, although HIV-positive subjects did not share with HIV-negative injectors. Sharing of syringes was positively associated with discordant HIV status (OR = 1.85) and negatively with discordant HCV status (OR = 0.65), but both results were not statistically significant. Sharing of drug preparation equipment was positively associated with both discordant HIV (OR = 1.61) and HCV (OR = 1.18) status, but both results were non-significant. Factors such as large injecting networks, frequent mutual injections, younger age, and male gender were stronger predictors of equipment sharing. In conclusion, IDUs do not appear to discriminate drug equipment sharing partners based at least on their HCV infection status. The results warrant greater screening to raise awareness of infection status, post-test counselling to promote status disclosure among partners, and skill-building to avoid equipment sharing between discordant partners.
doi:10.1080/00365540902721376
PMCID: PMC2929251  PMID: 19172434 CAMSID: cams1471
15.  Overadjustment Bias and Unnecessary Adjustment in Epidemiologic Studies 
Epidemiology (Cambridge, Mass.)  2009;20(4):488-495.
Overadjustment is defined inconsistently. This term is meant to describe control (eg, by regression adjustment, stratification, or restriction) for a variable that either increases net bias or decreases precision without affecting bias. We define overadjustment bias as control for an intermediate variable (or a descending proxy for an intermediate variable) on a causal path from exposure to outcome. We define unnecessary adjustment as control for a variable that does not affect bias of the causal relation between exposure and outcome but may affect its precision. We use causal diagrams and an empirical example (the effect of maternal smoking on neonatal mortality) to illustrate and clarify the definition of overadjustment bias, and to distinguish overadjustment bias from unnecessary adjustment. Using simulations, we quantify the amount of bias associated with overadjustment. Moreover, we show that this bias is based on a different causal structure from confounding or selection biases. Overadjustment bias is not a finite sample bias, while inefficiencies due to control for unnecessary variables are a function of sample size.
doi:10.1097/EDE.0b013e3181a819a1
PMCID: PMC2744485  PMID: 19525685
16.  Quantification of collider-stratification bias and the birthweight paradox 
Summary
The ‘birthweight paradox’ describes the phenomenon whereby birthweight-specific mortality curves cross when stratified on other exposures, most notably cigarette smoking. The paradox has been noted widely in the literature and numerous explanations and corrections have been suggested. Recently, causal diagrams have been used to illustrate the possibility for collider-stratification bias in models adjusting for birthweight. When two variables share a common effect, stratification on the variable representing that effect induces a statistical relation between otherwise independent factors. This bias has been proposed to explain the birthweight paradox.
Causal diagrams may illustrate sources of bias, but are limited to describing qualitative effects. In this paper, we provide causal diagrams that illustrate the birthweight paradox and use a simulation study to quantify the collider-stratification bias under a range of circumstances. Considered circumstances include exposures with and without direct effects on neonatal mortality, as well as with and without indirect effects acting through birthweight on neonatal mortality. The results of these simulations illustrate that when the birthweight-mortality relation is subject to substantial uncontrolled confounding, the bias on estimates of effect adjusted for birthweight may be sufficient to yield opposite causal conclusions, i.e. a factor that poses increased risk appears protective. Effects on stratum-specific birthweight-mortality curves were considered to illustrate the connection between collider-stratification bias and the crossing of the curves. The simulations demonstrate the conditions necessary to give rise to empirical evidence of the paradox.
doi:10.1111/j.1365-3016.2009.01053.x
PMCID: PMC2743120  PMID: 19689488
collider-stratification bias; birthweight; directed acyclic graphs; neonatal nortality
17.  Z-scores and the birthweight paradox 
Summary
Investigators have long puzzled over the observation that low-birthweight babies of smokers tend to fare better than low-birthweight babies of non-smokers. Similar observations have been made with regard to factors other than smoking status, including socio-economic status, race and parity. Use of standardised birthweights, or birthweight z-scores, has been proposed as an approach to resolve the crossing of the curves that is the hallmark of the so-called birthweight paradox. In this paper, we utilise directed acyclic graphs, analytical proofs and an extensive simulation study to consider the use of z-scores of birthweight and their effect on statistical analysis. We illustrate the causal questions implied by inclusion of birthweight in statistical models, and illustrate the utility of models that include birthweight or z-scores to address those questions.
Both analytically and through a simulation study we show that neither birthweight nor z-score adjustment may be used for effect decomposition. The z-score approach yields an unbiased estimate of the total effect, even when collider-stratification would adversely impact estimates from birthweight-adjusted models; however, the total effect could have been estimated more directly with an unadjusted model. The use of z-scores does not add additional information beyond the use of unadjusted models. Thus, the ability of z-scores to successfully resolve the paradoxical crossing of mortality curves is due to an alteration in the causal parameter being estimated (total effect), rather than adjustment for confounding or effect decomposition or other factors.
doi:10.1111/j.1365-3016.2009.01054.x
PMCID: PMC2742985  PMID: 19689489
birthweight; birthweight paradox; simulation; directed acyclic graphs; z-scores
18.  The double jeopardy of clustered measurement and cluster randomisation 
Michael S Kramer and colleagues suggest that double clustering might explain the negative results of some cluster randomised trials and describe some strategies for avoiding the problem
doi:10.1136/bmj.b2900
PMCID: PMC2730439  PMID: 19700507
19.  An Outcome-based Approach for the Creation of Fetal Growth Standards: Do Singletons and Twins Need Separate Standards? 
American Journal of Epidemiology  2009;169(5):616-624.
Contemporary fetal growth standards are created by using theoretical properties (percentiles) of birth weight (for gestational age) distributions. The authors used a clinically relevant, outcome-based methodology to determine if separate fetal growth standards are required for singletons and twins. All singleton and twin livebirths between 36 and 42 weeks’ gestation in the United States (1995–2002) were included, after exclusions for missing information and other factors (n = 17,811,922). A birth weight range was identified, at each gestational age, over which serious neonatal morbidity and neonatal mortality rates were lowest. Among singleton males at 40 weeks, serious neonatal morbidity/mortality rates were lowest between 3,012 g (95% confidence interval (CI): 3,008, 3,018) and 3,978 g (95% CI: 3,976, 3,980). The low end of this optimal birth weight range for females was 37 g (95% CI: 21, 53) less. The low optimal birth weight was 152 g (95% CI: 121, 183) less for twins compared with singletons. No differences were observed in low optimal birth weight by period (1999–2002 vs. 1995–1998), but small differences were observed for maternal education, race, parity, age, and smoking status. Patterns of birth weight-specific serious neonatal morbidity/neonatal mortality support the need for plurality-specific fetal growth standards.
doi:10.1093/aje/kwn374
PMCID: PMC2640160  PMID: 19126584
birth weight; fetal development; gestational age; infant mortality; morbidity
20.  Social Network-Related Risk Factors for Bloodborne Virus Infections Among Injection Drug Users Receiving Syringes through Secondary Exchange 
Journal of Urban Health   2007;85(1):77-89.
Secondary syringe exchange (SSE) refers to the exchange of sterile syringes between injection drug users (IDUs). To date there has been limited examination of SSE in relation to the social networks of IDUs. This study aimed to identify characteristics of drug injecting networks associated with the receipt of syringes through SSE. Active IDUs were recruited from syringe exchange and methadone treatment programs in Montreal, Canada, between April 2004 and January 2005. Information on each participant and on their drug-injecting networks was elicited using a structured, interviewer-administered questionnaire. Subjects’ network characteristics were examined in relation to SSE using regression models with generalized estimating equations. Of 218 participants, 126 were SSE recipients with 186 IDUs in their injecting networks. The 92 non-recipients reported 188 network IDUs. Networks of SSE recipients and non-recipients were similar with regard to network size and demographics of network members. In multivariate analyses adjusted for age and gender, SSE recipients were more likely than non-recipients to self-report being HIV-positive (OR = 3.56 [1.54–8.23]); require or provide help with injecting (OR = 3.74 [2.01–6.95]); have a social network member who is a sexual partner (OR = 1.90 [1.11–3.24]), who currently attends a syringe exchange or methadone program (OR = 2.33 [1.16–4.70]), injects daily (OR = 1.77 [1.11–2.84]), and shares syringes with the subject (OR = 2.24 [1.13–4.46]). SSE is associated with several injection-related risk factors that could be used to help focus public health interventions for risk reduction. Since SSE offers an opportunity for the dissemination of important prevention messages, SSE-based networks should be used to improve public health interventions. This approach can optimize the benefits of SSE while minimizing the potential risks associated with the practice of secondary exchange.
doi:10.1007/s11524-007-9225-z
PMCID: PMC2430130  PMID: 18038211
HIV; Hepatitis C; Injection drug use; Social network; Secondary syringe exchange; Syringe sharing
21.  Reducing bias through directed acyclic graphs 
Background
The objective of most biomedical research is to determine an unbiased estimate of effect for an exposure on an outcome, i.e. to make causal inferences about the exposure. Recent developments in epidemiology have shown that traditional methods of identifying confounding and adjusting for confounding may be inadequate.
Discussion
The traditional methods of adjusting for "potential confounders" may introduce conditional associations and bias rather than minimize it. Although previous published articles have discussed the role of the causal directed acyclic graph approach (DAGs) with respect to confounding, many clinical problems require complicated DAGs and therefore investigators may continue to use traditional practices because they do not have the tools necessary to properly use the DAG approach. The purpose of this manuscript is to demonstrate a simple 6-step approach to the use of DAGs, and also to explain why the method works from a conceptual point of view.
Summary
Using the simple 6-step DAG approach to confounding and selection bias discussed is likely to reduce the degree of bias for the effect estimate in the chosen statistical model.
doi:10.1186/1471-2288-8-70
PMCID: PMC2601045  PMID: 18973665
22.  The interpretation of systematic reviews with meta-analyses: an objective or subjective process? 
Background
Discrepancies between the conclusions of different meta-analyses (quantitative syntheses of systematic reviews) are often ascribed to methodological differences. The objective of this study was to determine the discordance in interpretations when meta-analysts are presented with identical data.
Methods
We searched the literature for all randomized clinical trials (RCT) and review articles on the efficacy of intravenous magnesium in the early post-myocardial infarction period. We organized the articles chronologically and grouped them in packages. The first package included the first RCT, and a summary of the review articles published prior to first RCT. The second package contained the second and third RCT, a meta-analysis based on the data, and a summary of all review articles published prior to the third RCT. Similar packages were created for the 5th RCT, 10th RCT, 20th RCT and 23rd RCT (all articles). We presented the packages one at a time to eight different reviewers and asked them to answer three clinical questions after each package based solely on the information provided. The clinical questions included whether 1) they believed magnesium is now proven beneficial, 2) they believed magnesium will eventually be proven to be beneficial, and 3) they would recommend its use at this time.
Results
There was considerable disagreement among the reviewers for each package, and for each question. The discrepancies increased when the heterogeneity of the data increased. In addition, some reviewers became more sceptical of the effectiveness of magnesium over time, and some reviewers became less sceptical.
Conclusion
The interpretation of the results of systematic reviews with meta-analyses includes a subjective component that can lead to discordant conclusions that are independent of the methodology used to obtain or analyse the data.
doi:10.1186/1472-6947-8-19
PMCID: PMC2408567  PMID: 18495019
23.  The joint influence of marital status, interpregnancy interval, and neighborhood on small for gestational age birth: a retrospective cohort study 
Background
Interpregnancy interval (IPI), marital status, and neighborhood are independently associated with birth outcomes. The joint contribution of these exposures has not been evaluated. We tested for effect modification between IPI and marriage, controlling for neighborhood.
Methods
We analyzed a cohort of 98,330 live births in Montréal, Canada from 1997–2001 to assess IPI and marital status in relation to small for gestational age (SGA) birth. Births were categorized as subsequent-born with short (<12 months), intermediate (12–35 months), or long (36+ months) IPI, or as firstborn. The data had a 2-level hierarchical structure, with births nested in 49 neighborhoods. We used multilevel logistic regression to obtain adjusted effect estimates.
Results
Marital status modified the association between IPI and SGA birth. Being unmarried relative to married was associated with SGA birth for all IPI categories, particularly for subsequent births with short (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.31–1.95) and intermediate (OR 1.48, 95% CI 1.26–1.74) IPIs. Subsequent births had a lower likelihood of SGA birth than firstborns. Intermediate IPIs were more protective for married (OR 0.50, 95% CI 0.47–0.54) than unmarried mothers (OR 0.65, 95% CI 0.56–0.76).
Conclusion
Being unmarried increases the likelihood of SGA birth as the IPI shortens, and the protective effect of intermediate IPIs is reduced in unmarried mothers. Marital status should be considered in recommending particular IPIs as an intervention to improve birth outcomes.
doi:10.1186/1471-2393-8-7
PMCID: PMC2268912  PMID: 18307804
24.  Correction: five-year predictors of physical activity decline among adults in low-income communities: a prospective study 
After publication it was brought to our attention that the information for one of the variables in Table 1 was incorrect (Weiss, O'Loughlin et al. International Journal of Behavioral Nutrition and Physical Activity 2007, 4:2). The variable in question is "Use of a neighborhood facility for activity". In the first column, the first row should read "yes", and the second row, "no". In the second column, the first row should read 25.8 (41) and the second row, 41.3 (152).
Unadjusted and adjusted Odds Ratios for potential predictors of becoming inactive [1].
aBody Mass Index
* Not included in final model
doi:10.1186/1479-5868-4-23
PMCID: PMC1896097
25.  Five-year predictors of physical activity decline among adults in low-income communities: a prospective study 
Background
Obesity in North America is now endemic, and increased understanding of the determinants of physical inactivity is critical. This analysis identified predictors of declines in physical activity over 5 years among adults in low-income, inner-city neighbourhoods.
Methods
Data on leisure time physical activity were collected in telephone interviews in 1992 and 1997 from 765 adults (47% of baseline respondents), as part of the evaluation of a community-based cardiovascular disease risk reduction program.
Results
One-third of 527 participants who were physically active at baseline, were inactive in 1997. Predictors of becoming inactive included female sex (OR = 1.63 95% CI (1.09, 2.43)), older age (1.02 (1.01, 1.04)), higher BMI (1.57 (1.03, 2.40)), poor self-rated health (1.39 (1.05, 1.84)), lower self-efficacy for physical activity (1.46 (1.00, 2.14)), and not using a neighborhood facility for physical activity (1.61 (1.02, 2.14)).
Conclusion
These results highlight the fact that a variety of variables play a role in determining activity level, from demographic variables such as age and sex, to psychosocial and environmental variables. In addition, these results highlight the important role that other health-related variables may play in predicting physical activity level, in particular the observed association between baseline BMI and the increased risk of becoming inactive over time. Lastly, these results demonstrate the need for multi-component interventions in low-income communities, which target a range of issues, from psychosocial factors, to features of the physical environment.
doi:10.1186/1479-5868-4-2
PMCID: PMC1785385  PMID: 17233904

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