A Call for Caution in Use of Pertussis Vaccine Effectiveness Studies to Estimate Waning Immunity: A Canadian Immunization Research Network Study.

BACKGROUND: Vaccine effectiveness (VE) studies provide essential evidence on waning vaccine-derived immunity, a major threat to pertussis control. We evaluated how study design affects estimates by comparing 2 case-control studies conducted in Ontario, Canada. METHODS: We compared results from a test-negative design (TND) with a frequency-matched design (FMD) case-control study using pertussis cases from 2005-2015. In the first study, we identified test-negative controls from the public health laboratory that diagnosed cases and, in the second, randomly selected controls from patients attending the same physicians that reported cases, frequency matched on age and year. We compared characteristics of cases and controls using standardized differences. RESULTS: In both designs, VE estimates for the early years postimmunization were consistent with clinical trials (TND, 84%; FMD, 89% at 1-3 years postvaccination) but diverged as time since last vaccination increased (TND, 41%; FMD, 74% by 8 years postvaccination). Overall, we observed lower VE and faster waning in the TND than the FMD. In the TND but not FMD, controls differed from cases in important confounders, being younger, having more comorbidities, and higher healthcare use. Differences between the controls of each design were greater than differences between cases. TND controls were more likely to be unvaccinated or incompletely vaccinated than FMD controls (P < .001). CONCLUSIONS: The FMD adjusted better for healthcare-seeking behavior than the TND. Duration of protection from pertussis vaccines is unclear because estimates vary by study design. Caution should be exercised by experts, researchers, and decision makers when evaluating evidence on optimal timing of boosters.

Risk of Invasive Cervical Cancer Among Immigrants in Ontario, Canada.

BACKGROUND: The risk of invasive cervical cancer (ICC) varies throughout the world. We aimed to compare the risk of this invasive disease among immigrants arriving in Ontario with that of the general female population of Ontario. METHODS: We used an exposure-control matched design. We identified females from the Immigration, Refugees, and Citizenship Canada (IRCC) database with arrival in Ontario, and whose first eligibility for the Ontario Health Insurance Plan according to its Registered Persons Database fell between July 1, 1991, and June 30, 2008, at age 20 years or older, and matched two female controls on year of birth. We identified cases of ICC between the index date and December 31, 2014. Crude rates and relative rates of ICC were calculated. Multivariable extended Cox regression models were then implemented. RESULTS: The crude rate of ICC was 0.032 per 100 000 person-years for immigrants and 0.037 for controls. Immigrants who were born in certain countries showed a higher risk of ICC; Russia had a relative rate of 1.736 compared with a relative rate of 0.221 among those born in Iran. Among immigrants, the age-adjusted HR was 0.76 (95% CI 0.63-0.92) after 10 years of residency when compared with controls. Immigrants aged 20 to 39 years had a lower risk of ICC compared with controls of equivalent age, and immigrants aged ≥40 years had a higher risk of ICC. CONCLUSIONS: The risk of ICC among immigrants in Ontario varies by age, country of birth, and time since immigration.

The use of permutation tests for the analysis of parallel and stepped-wedge cluster-randomized trials.

We investigate the use of permutation tests for the analysis of parallel and stepped-wedge cluster-randomized trials. Permutation tests for parallel designs with exponential family endpoints have been extensively studied. The optimal permutation tests developed for exponential family alternatives require information on intraclass correlation, a quantity not yet defined for time-to-event endpoints. Therefore, it is unclear how efficient permutation tests can be constructed for cluster-randomized trials with such endpoints. We consider a class of test statistics formed by a weighted average of pair-specific treatment effect estimates and offer practical guidance on the choice of weights to improve efficiency. We apply the permutation tests to a cluster-randomized trial evaluating the effect of an intervention to reduce the incidence of hospital-acquired infection. In some settings, outcomes from different clusters may be correlated, and we evaluate the validity and efficiency of permutation test in such settings. Lastly, we propose a permutation test for stepped-wedge designs and compare its performance with mixed-effect modeling and illustrate its superiority when sample sizes are small, the underlying distribution is skewed, or there is correlation across clusters. Copyright © 2017 John Wiley & Sons, Ltd.

Risk of colorectal cancer among immigrants to Ontario, Canada.

BACKGROUND: The risk of colorectal cancer (CRC) varies around the world and between females and males. We aimed to compare the risk of CRC among immigrants to Ontario, Canada, to its general population. METHODS: We used an exposure-control matched design. We identified persons in the Immigration, Refugees and Citizenship Canada Permanent Resident Database with first eligibility for the Ontario Health Insurance Plan between July 1, 1991 and June 30, 2008 at age 40 years or older, and matched five controls by year of birth and sex on the immigrant's first eligibility date. We identified CRC from the Ontario Cancer Registry between the index date and December 31, 2014. All analyses were stratified by sex. We calculated crude and relative rates of CRC. We estimated risk of CRC over time by the Kaplan-Meier method and compared immigrants to controls in age and sex stratified strata using log-rank tests. We modeled the hazard of CRC using Cox proportional hazards regression, accounting for within-cluster correlation by a robust sandwich variance estimation approach, and assessed an interaction with time since eligibility. RESULTS: Among females, 1877 cases of CRC were observed among 209,843 immigrants, and 16,517 cases among 1,049,215 controls; the crude relative rate among female immigrants was 0.623. Among males, 1956 cases of CRC were observed among 191,792 immigrants and 18,329 cases among 958,960 controls; the crude relative rate among male immigrants was 0.582.. Comparing immigrants to controls in all age and sex stratified strata, the log rank test p < 0.0001 except for females aged > = 75 years at index, where p = 0.01. The age-adjusted hazard ratio (HR) for CRC among female immigrants was 0.63 (95% CI 0.59, 0.67) during the first 10 years, and 0.66 (95% CI 0.59, 0.74) thereafter. Among male immigrants the age-adjusted HR = 0.55 (95% CI 0.52, 0.59) during the first 10 years and increased to 0.63 (95% CI 0.57, 0.71) thereafter. The adjusted HR > = 1 only among immigrants born in Europe and Central Asia. CONCLUSIONS: The risk of CRC among immigrants to Ontario relative to controls varies by origin and over time since immigration.

Maternal Childhood Sexual Trauma and Early Parenting: Prenatal and Postnatal Associations.

Existing research suggests that approximately 19% of females experience childhood sexual trauma (CST). Little is known, however, about the parenting behaviour of mothers who have experienced CST. Using propensity-matched controls, the present study examines prenatal psychosocial distress, postnatal depressive symptomatology, and caregiving behaviours of women reporting CST at or before the age of 14. Data for these analyses were obtained from mother reports and from observational protocols from a longitudinal study of low-income, rural families. Propensity score methodology was used to create a contrast group matched on family of origin variables in an effort to isolate and examine the long-term associations of CST beyond the effects of other childhood adversities such as poverty. Study findings provide evidence that women with CST histories report greater prenatal psychosocial distress compared to women without trauma histories. Findings further provide evidence for a spillover process from prenatal distress to the broader caregiving system including less sensitive parenting through postnatal depressive symptoms for women with CST histories. These results highlight the importance of screening for CST and psychosocial distress and depression prenatally. Interventions for women with CST histories and directions for future study are proposed.

Adjusting for matching and covariates in linear discriminant analysis.

In studies that compare several diagnostic or treatment groups, subjects may not only be measured on a certain set of feature variables, but also be matched on a number of demographic characteristics and measured on additional covariates. Linear discriminant analysis (LDA) is sometimes used to identify which feature variables best discriminate among groups, while accounting for the dependencies among the feature variables. We present a new approach to LDA for multivariate normal data that accounts for the subject matching used in a particular study design, as well as covariates not used in the matching. Applications are given for post-mortem tissue data with the aim of comparing neurobiological characteristics of subjects with schizophrenia with those of normal controls, and for a post-mortem tissue primate study comparing brain biomarker measurements across three treatment groups. We also investigate the performance of our approach using a simulation study.

Analysis of incidence and prognosis from 'extreme' case-control designs.

The significant investment in measuring biomarkers has prompted investigators to improve cost-efficiency by sub-sampling in non-standard study designs. For example, investigators studying prognosis may assume that any differences in biomarkers are likely to be most apparent in an extreme sample of the earliest deaths and the longest-surviving controls. Simple logistic regression analysis of such data does not exploit the information available in the survival time, and statistical methods that model the sampling scheme may be more efficient. We derive likelihood equations that reflect the complex sampling scheme in unmatched and matched 'extreme' case-control designs. We investigated the performance and power of the method in simulation experiments, with a range of underlying hazard ratios and study sizes. Our proposed method resulted in hazard ratio estimates close to those obtained from the full cohort. The standard error estimates also performed well when compared with the empirical variance. In an application to a study investigating markers for lethal prostate cancer, an extreme case-control sample of lethal cases and the longest-surviving controls provided estimates of the effect of Gleason score in close agreement with analysis of all the data. By using the information in the sampling design, our method enables efficient and valid estimation of the underlying hazard ratio from a study design that is intuitive and easily implemented.

Effects of gestational ambient extreme temperature exposures on the risk of preterm birth in China: A sibling-matched study based on a multi-center prospective cohort.

BACKGROUND: Previous epidemiological findings on extreme temperature and preterm birth (PTB) were heterogeneous, especially for extreme cold exposure. Measured and unmeasured individual-level factors such as genetic factors or lifecourse exposures may constitute important contributors but have not been addressed. OBJECTIVES: We aimed to examine the association of gestational heat and cold exposure with PTB using a novel sibling-matched study. METHODS: Based on a multi-center population-based birth cohort across 16 counties in China, we included 10,826 sibling pairs born from March 2013 to December 2018. Conditional logistic and Cox Proportional Hazard regression models were used to estimate the effects of heat and cold exposure on PTB in each trimester, one and four weeks before delivery and the entire pregnancy. We also tested the heterogeneity in the association of temperature with PTB between siblings. FINDINGS: Exposure to heat during the third trimester and the entire pregnancy increased the risk of PTB. For heat (> 90th) defined with mean temperature, the odds ratios were 2.32 (1.63, 3.30) and 3.19 (2.22, 4.58), respectively. Cold exposure (< 10th) during the first, the third, and the entire pregnancy was associated with a higher PTB risk, with ORs (95%CIs) of 2.04 (1.43, 2.90), 3.13 (2.14, 4.58), and 4.26 (2.94, 6.19), respectively. We found slightly stronger associations of heat exposure during the entire pregnancy with the firstborn PTB, and stronger associations of cold exposure during one week and four weeks before delivery with secondborn PTB. CONCLUSIONS: Using a sibling-matched study, we took into account some mother-level unobserved confounding. Our research strengthens the evidence that gestational exposure to heat and cold increases the risk of PTB. Our findings may have important implications for improving the health of newborns in the context of climate change.

Desloratadine Use During Pregnancy and Risk of Adverse Fetal Outcomes: A Nationwide Cohort Study.

BACKGROUND: Desloratadine is a frequently used drug for the treatment of allergic disorders, which often also require treatment during pregnancy. However, information on the fetal safety of desloratadine use during pregnancy is limited. OBJECTIVE: To investigate the association between desloratadine use during pregnancy and adverse fetal outcomes. METHODS: From a cohort of 1,287,668 pregnancies identified in the Danish nationwide registries in the study period 2001 to 2016, users of desloratadine and loratadine during pregnancy were matched in a 1:1 ratio based on propensity scores to compare the risk of adverse fetal outcomes. We compared the risk of the primary outcomes major birth defects (among a total of 3348 pregnancies) and spontaneous abortion (5498 pregnancies) and the secondary outcomes preterm birth (5280 pregnancies), small size for gestational age (SGA) for birth weight (5436 pregnancies), and stillbirth (6776 pregnancies). Logistic regression was used to estimate the prevalence odds ratio (OR) of major birth defects, preterm birth, and SGA, and Cox regression to estimate the hazard ratio (HR) of spontaneous abortion and stillbirth. Sensitivity analyses included comparing with cetirizine use in pregnancy and with pregnancies unexposed to desloratadine but with prior use as additional comparator groups. RESULTS: Use of desloratadine in pregnancy was not associated with a significant increased risk of major birth defects (prevalence OR, 1.07; 95% confidence interval [CI], 0.77-1.50), spontaneous abortion (HR, 1.15; 95% CI, 0.96-1.37), preterm birth (prevalence OR, 0.84; 95% CI, 0.67-1.05), SGA (prevalence OR, 0.97; 95% CI, 0.80-1.16), or stillbirth (HR, 0.91; 95% CI, 0.31-2.70) compared with loratadine use in pregnancy. Sensitivity analyses, including those with the use of additional comparator groups, showed similar results. CONCLUSION: Use of desloratadine during pregnancy was not associated with a statistically significant increased risk of adverse fetal outcomes as compared with loratadine. Results indicate that the fetal safety profile of desloratadine is similar to the currently recommended second-generation antihistamines during pregnancy.

The missing indicator approach for censored covariates subject to limit of detection in logistic regression models.

PURPOSE: In several biomedical studies, one or more exposures of interest may be subject to nonrandom missingness because of the failure of the measurement assay at levels below its limit of detection. This issue is commonly encountered in studies of the metabolome using tandem mass spectrometry-based technologies. Owing to a large number of metabolites measured in these studies, preserving statistical power is of utmost interest. In this article, we evaluate the small sample properties of the missing indicator approach in logistic and conditional logistic regression models. METHODS: For nested case-control or matched case control study designs, we evaluate the bias, power, and type I error associated with the missing indicator method using simulation. We compare the missing indicator approach to complete case analysis and several imputation approaches. RESULTS: We show that under a variety of settings, the missing indicator approach outperforms complete case analysis and other imputation approaches with regard to bias, mean squared error, and power. CONCLUSIONS: For nested case-control and matched study designs of modest sample sizes, the missing indicator model minimizes loss of information and thus provides an attractive alternative to the oft-used complete case analysis and other imputation approaches.

Is the matched extreme case-control design more powerful than the nested case-control design?

For time-to-event data, the study sample is commonly selected using the nested case-control design in which controls are selected at the event time of each case. An alternative sampling strategy is to sample all controls at the same (pre-specified) time, which can either be at the last event time or further out in time. Such controls are the long-term survivors and may therefore constitute a more 'extreme' comparison group and be more informative than controls from the nested case-control design. We investigate this potential information gain by comparing the power of various 'extreme' case-control designs with that of the nested case-control design using simulation studies. We derive an expression for the theoretical average information in a nested and extreme case-control pair for the situation of a single binary exposure. Comparisons reveal that the efficiency of the extreme case-control design increases when the controls are sampled further out in time. In an application to a study of dementia, we identified Apolipoprotein E as a risk factor using a 1:1 extreme case-control design, which provided a hazard ratio estimate with a smaller standard error than that of a 2:1 nested case-control design.

Semiparametric Additive Model for Estimating Risk Difference in Multicenter Studies.

Many cancer studies are conducted in multiple centers. While they have the advantage of more patients and larger population, center-to-center heterogeneity could be significant such that it cannot be ignored in analysis. In this paper, we propose semiparametric additive risk models with a general link function to estimate risk effects while accounting for center-specific baseline function. We propose an estimating equation for inference and show that the derived estimators are consistent and asymptotically normal. Simulation studies demonstrate good small-sample performance of the proposed method. We apply the method to analyze data from the Study of Left Ventricular Dysfunction (SOLVD) in 1990 and discuss application to one-to-one matched design.

Maternal Childhood Sexual Trauma, Child Directed Aggression, Parenting Behavior, and the Moderating Role of Child Sex.

Using propensity-matched controls, the present study examines the associations between maternal report of child-directed aggression and observed parenting behavior across early childhood for women with and without childhood sexual trauma histories. The moderating role of child sex was also examined. The sample (n=204) is from a longitudinal study of rural poverty exploring the ways in which child, family, and contextual factors shape development over time. After controlling for numerous factors including child and primary caregiver covariates, findings reveal that childhood sexual trauma is related to sensitive parenting behavior and child-directed aggression. Findings further revealed that child sex moderates the relation between sexual trauma history and maternal behavior towards children. Implications for interventions for mothers with childhood sexual trauma histories and directions for future study are proposed.

Neurobiological bases of reading disorder Part I: Etiological investigations.

While many studies have focused on identifying the neural and behavioral characteristics of decoding-based reading disorder (RD, aka developmental dyslexia), the etiology of RD remains largely unknown and understudied. Because the brain plays an intermediate role between genetic factors and behavioral outcomes, it is promising to address causality from a neural perspective. In the current, Part I of the two-part review, we discuss neuroimaging approaches to addressing the causality issue and review the results of studies that have employed these approaches. We assume that if a neural signature were associated with RD etiology, it would (a) manifest across comparisons in different languages, (b) be experience independent and appear in comparisons between RD and reading-matched controls, (c) be present both pre- and post-intervention, (d) be found in at-risk, pre-reading children and (e) be associated with genetic risk. We discuss each of these five characteristics in turn and summarize the studies that have examined each of them. The available literature provides evidence that anomalies in left temporo-parietal cortex, and possibly occipito-temporal cortex, may be closely related to the etiology of RD. Improved understanding of the etiology of RD can help improve the accuracy of early detection and enable targeted intervention of cognitive processes that are amenable to change, leading to improved outcomes in at-risk or affected populations.

Childhood sexual trauma and subsequent parenting beliefs and behaviors.

Using propensity-matched controls, the present study examines the long-term adjustment of women reporting childhood sexual trauma (CST) at or before the age of 14 in terms of parenting efficacy and parenting behavior. Data for these analyses were obtained from mother reports and from observational protocols from a longitudinal study of low-income, rural families. The novel use of propensity-matched controls to create a control group matched on family of origin variables provides evidence that when women with CST are compared with the matched comparison women, females who experienced CST show poorer functioning across multiple domains of parenting (sensitivity, harsh intrusiveness, boundary dissolution), but not in parenting efficacy. Follow-up moderation analyses suggest that the potential effects of trauma on parenting behaviors are not attenuated by protective factors such as higher income, higher education, or stable adult relationships. Implications for interventions with childhood sexual trauma histories and directions for future study are proposed.

Is the impaired N170 print tuning specific to developmental dyslexia? A matched reading-level study with poor readers and dyslexics.

Left N170 print tuning has been associated with visual expertise for print and has been reported to be impaired in dyslexics, using age matched designs. This is the first time N170 print tuning has been compared in adult dyslexics and adult poor readers, matched in reading level. Participants performed a lexical decision task using both word-like stimuli and symbol strings. In contrast to dyslexics, poor readers displayed similar N170 tuning to control expert readers, suggesting that impaired N170 specialization is a hallmark of developmental dyslexia. Our findings provide electrophysiological support for dyslexia being the result of abnormal specialization of the left occipito-temporal areas involved in the expert processing of print. Furthermore, as shown by correlations data and in accordance with the phonological mapping deficit theory, the impaired visual expertise for print described in dyslexics may have been caused by their core phonological deficits.