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Purpose Current newborn screening (NBS) for mucopolysaccharidosis type I (MPSI) has very high false positive rates and low positive predictive values (PPVs). To improve the accuracy of presymptomatic prediction for MPSI, we propose an NBS tool based on known biomarkers, alpha‐L‐iduronidase enzyme activity (IDUA) and level of the glycosaminoglycan (GAG) heparan sulfate (HS). Methods We developed the NBS tool using measures from dried blood spots (DBS) of 5000 normal newborns from Gifu Prefecture, Japan. The tool's predictive accuracy was tested on the newborn DBS from these infants and from seven patients who were known to have early‐onset MPSI (Hurler's syndrome). Bivariate analyses of the standardized natural logarithms of IDUA and HS levels were employed to develop the tool. Results Every case of early‐onset MPSI was predicted correctly by the tool. No normal newborn was incorrectly identified as having early‐onset MPSI, whereas 12 normal newborns were so incorrectly identified by the Gifu NBS protocol. The PPV was estimated to be 99.9%. Conclusions Bivariate analysis of IDUA with HS in newborn DBS can accurately predict early MPSI symptoms, control false positive rates, and enhance presymptomatic treatment. This bivariate analysis‐based approach, which was developed for Krabbe disease, can be extended to additional screened disorders.

Objectives To develop a quality of life (QOL) survey for Krabbe disease (KD), and to thereby improve understanding of its phenotypic expression and response to treatment. Methods The survey, the Leukodystrophy Quality of Life Assessment (LQLA) and the Vineland Adaptive Behavior Scales were co‐administered to 33 patients or their caretakers. These included the phenotypes of early infantile KD (EIKD; 0‐6 months old at onset), late infantile cases (LIKD; 7‐12 months old at onset), and cases that emerged after 12 months old, late onset (LOKD). The sample included cases with and without stem cell transplantation (SCT). Reliability and concurrent validity were assessed for overall and subscale scores. Analysis of variance tested differences in QOL between phenotypes and transplant groups (none, pre‐, post‐symptom). Results Good concurrent validity with the Vineland was shown for total, communication, daily activity, social, and motor scales and good reliability was observed. LOKD cases had better communication skills than either EIKD or LIKD and better overall QOL than EIKD. Analyses of individual items showed that communication items, mostly, contributed significantly to phenotype differences. Presymptomatic SCT significantly improved QOL compared to postsymptomatic SCT or no treatment. Presymptomatically treated patients had near‐normal total scores. Conclusions The LQLA is valid and reliable. Despite small sample size, phenotypic demarcation was determined to be due mainly to differences in communication skills. There was a relative enhancement of QOL in LOKD patients, and in those who had presymptomatic SCT. These results apply to the current controversy about recommendations for newborn screening for this condition.

In this paper, we propose an extension of the frailty modeling to analyze the recurrent events data. We proposed a class of models, based on nonlinear mixed effects modeling, that takes into consideration of the between subject heterogeneity in the model. We propose an estimation method for estimating parameters of the proposed model and their standard deviations. The estimating equations are shown to give consistent estimates under commonly satisfied regularity conditions. A method for consistently estimating the covariance matrix of between subject random effects is also given. We prove the consistency and asymptotical normality of the estimators. We apply the proposed generalized frailty model to the Mammary Tumor data of 48 rats that was previously analyzed by Gail et al. (1980) and Cook and Lawless (2007). We compare the result of the our proposed model with results from the commonly used fixed effect model and frailty model. Both fixed effects model and frailty models result in biased estimates of the variance function for cumulative number of tumors. Simulation results suggest that the proposed generalized frailty model and estimation method is computationally feasible and provides unbiased estimates of the parameters and standard errors of their estimators.

To use national mortality and state death certificate records to estimate disease specific mortality rates among pediatric and adult populations for 23 leukodystrophies (LDs) with pediatric forms. Additionally, to calculate yearly prevalence and caseload of the most severe LD cases that will eventually result in pediatric death (i.e., pediatric fatality cases). Death certificate records describing cause of death were collected from states based on 10 ICD-10 codes associated with the 23 LDs. Deaths in the U.S. with these codes were distributed into categories based on proportions identified in state death certificate data. Mortality rates, prevalence, and caseload were calculated from resulting expected numbers, population sizes, and average lifetimes. An estimated 1.513 per 1,000,000 0-17 year old's died of these LDs at average age 5.2 years and 0.194 for those ≥18 at an average age of 42.3 years. Prevalence of pediatric fatality cases of these LDs declined from 1999 through 2007 and then remained constant at 6.2 per million children per year through 2012. Epidemiological information, currently lacking for rare diseases, is useful to newborn screening programs, research funding agencies, and care centers for LD patients. Methods used here are generally useful for studying rare diseases.

Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.

Krabbe's disease (KD) is a severe neurodegenerative disorder affecting white matter in the brain and peripheral nerves. Transplantation of hematopoietic stem cells (HSCT), although not curative, has been shown to extend survival and alleviate neurodevelopmental symptoms when treatment precedes the onset of symptoms. Existing evidence, although not tested statistically, seems clearly to show that postsymptomatic transplantation does not improve neurodevelopmental outcomes. The impact of postsymptomatic HSCT treatment on survival, however, is an open question. This study uses a KD registry to examine the effect of HSCT on survival of symptomatic KD patients. Sixteen transplanted patients were matched by age of onset to 68 nontransplanted patients. The potential confounding effect of age of onset was, therefore, avoided. To quantify the effect of HSCT over time, we used Cox regression analysis, and we observed a sustained and nearly 2.2-fold risk of death from KD in patients who were not transplanted relative to those who were transplanted (one-tailed P = 0.0365; 95% lower bound = 1.07). The improvement of survival resulting from HSCT did not appear to depend on the age of symptom onset. Thus, these results establish a long-term, quantitative benefit of HSCT even in patients who are already experiencing symptoms. They also provide a benchmark for improved survival that can be used for potential new treatments for KD. © 2016 Wiley Periodicals, Inc.

Generalized Multiple Indicators, Multiple Causes Measurement Error Models (G-MIMIC ME) can be used to study the effects of an unobservable latent variable on a set of outcomes when the causes of the latent variables are unobserved. The errors associated with the unobserved causal variables can be due to either bias recall or day-to-day variability. Another potential source of error, the Berkson error, is due to individual variations that arise from the assignment of group data to individual subjects. In this article, we accomplish the following: (a) extend the classical linear MIMIC models to allow both Berkson and classical measurement errors where the distributions of the outcome variables belong in the exponential family, (b) develop likelihood based estimation methods using the MC-EM algorithm and (c) estimate the variance of the classical measurement error associated with the approximation of the amount of radiation dose received by atomic bomb survivors at the time of their exposure. The G-MIMIC ME model is applied to study the effect of genetic damage, a latent construct based on exposure to radiation, and the effect of radiation dose on physical indicators of genetic damage.

Purpose Newborn screening for Krabbe disease (KD) originated in New York State in 2006 but has proven to have a high false positive rate and low positive predictive value. To improve accuracy of presymptomatic prediction, we propose a screening tool based on two biomarkers, psychosine and galactocerebrosidase enzyme activity (GalC). Methods We developed the tool using measures from dried blood spots of 166 normal newborns and tested it on dried blood spot measures from 15 newborns who later developed KD, 8 newborns identified as "high risk" by the New York screening protocol but were disease-free at follow-up, and 3 symptomatic children with onset before 4 years of age. The tool was developed from the (1–10−6)100% prediction region of the natural logarithms of psychosine and GalC measures, assuming bivariate normality, and their univariate normal limits. Results Krabbe disease was predicted correctly for every patient who developed symptoms in infancy or early childhood. None of the high-risk patients were incorrectly identified as having early KD. Conclusion Bivariate analysis of psychosine and GalC in newborn blood spots can accurately predict early Krabbe symptoms, control false positive rates, and permit presymptomatic treatment.

In this article we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo EM (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group (GOG) study of significant cervical lesion (S-CL) diagnosis in women with atypical glandular cells of undetermined significance (AGC) to compare the diagnostic accuracy of a histology-based evaluation, a CA-IX biomarker-based test and a human papillomavirus (HPV) DNA test.

Background Estimates of ADHD diagnosis and stimulant medication use vary across studies. Few studies ascertain the teacher perspective on these rates.

Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.

Krabbe's disease (KD) is a severe neurodegenerative disorder affecting white matter in the brain and peripheral nerves. Transplantation of hematopoietic stem cells (HSCT), although not curative, has been shown to extend survival and alleviate neurodevelopmental symptoms when treatment precedes the onset of symptoms. Existing evidence, although not tested statistically, seems clearly to show that postsymptomatic transplantation does not improve neurodevelopmental outcomes. The impact of postsymptomatic HSCT treatment on survival, however, is an open question. This study uses a KD registry to examine the effect of HSCT on survival of symptomatic KD patients. Sixteen transplanted patients were matched by age of onset to 68 nontransplanted patients. The potential confounding effect of age of onset was, therefore, avoided. To quantify the effect of HSCT over time, we used Cox regression analysis, and we observed a sustained and nearly 2.2-fold risk of death from KD in patients who were not transplanted relative to those who were transplanted (one-tailed P = 0.0365; 95% lower bound = 1.07). The improvement of survival resulting from HSCT did not appear to depend on the age of symptom onset. Thus, these results establish a long-term, quantitative benefit of HSCT even in patients who are already experiencing symptoms. They also provide a benchmark for improved survival that can be used for potential new treatments for KD. © 2016 Wiley Periodicals, Inc.

In the absence of gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology-, and histology-based tests for significant cervical lesions (SCL) in US women with AGC-NOS Pap smear diagnoses. Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n = 122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX); and invasive histological diagnosis, were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity, and prevalence to obtain age-specific false-positive and false-negative rates. The histology-based test was nearly perfect (sensitivity = 1.00, CI = 0.98–1.00; specificity = 0.99, CI = 0.96–1.00). Otherwise, HC2 H-HPV performed best (sensitivity = 1.00, CI = 1.00–1.00; specificity = 0.87, CI = 0.79–0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17 %) at each age, while those of the histological diagnoses were low (

The majority of newborns screening positive for Krabbe disease have not exhibited the expected early infantile phenotype, with most clinically normal despite low galactocerebrosidase activity and two mutations. Most are expected to develop the later onset phenotypes. The World-Wide Krabbe Registry was developed in part to expand our understanding of the natural history of these rare variants. As of June 2011, 122 patients were enrolled in the registry: 62% manifested early infantile onset (previously reported), 10% manifested onset at 7-12 months (late infantile), 22% manifested onset at 13 months to 10 years (later onset), and 5% manifested adolescent/adult onset. Data on disease course, galactocerebrosidase activity, DNA mutations, and results of neurodiagnostic studies were obtained from questionnaires and medical records. Initial signs (late infantile) included loss of milestones and poor feeding, whereas later onset and adolescent/adult phenotypes presented with changes in gait. Elevated cerebrospinal fluid protein and abnormal magnetic resonance imaging results were present in most, but not all, patients at diagnosis. Phenotypic variability occurred in four sibships. Five-year and 10-year survivals for all later onset phenotypes were at least 50%. The later onset Krabbe phenotypes differ from those with early infantile disease, but no specific predictor of phenotype was identified.

article i nfo Objective. To describe trends in mortality rates, in New York State, due to cervical, endometrial and ovarian cancer and to assess how these rates varied with proximity to a comprehensive cancer treatment center or population density (rural/urban). Methods. Data were obtained from the Centers for Disease Control and Prevention (CDC)'s Compressed Mortality Files, Census Bureau records, and online maps. Poisson regression models were fitted to estimate death rates (mean number of deaths per 100,000 women per year) due to gynecologic cancer type. Trends in death rates were compared with respect to driving time to the nearest comprehensive cancer treatment center and population density, controlling for race, county income level, and age at death. Results. Cervical and endometrial but not ovarian death rates declined over time. For both cervical and endometrial cancers, death rates varied significantly with driving time and between rural and urban counties. In the case of cervical cancer, the decline over time was steeper in rural than in urban counties. For endometrial cancer, the decline steepened with increasing distance from a treatment center. Conclusion. Improvements in cervical and endometrial cancer mortality from 1979 to 2001 followed increases in gynecologic cancer treatment research efforts, number of specialists trained to treat such cases, and in the emphasis on gynecologic cancer in the training of physicians in general. Our results are consistent with an interpretation that the progressive actions by leaders in the gynecologic oncology profession during the late 1960's and early 1970's contributed to improvements in mortality rates in subsequent decades.

Summary This paper gives an introduction and overview to the often under-used measurement error model. The purpose is to provide a simple summary of problems that arise from measurement error and of the solutions that have been proposed. We start by describing how measurement error models occur in real-world situations. Then we proceed with defining the measurement error model, initially introducing the multivariate form of the model, and then, starting with the simplest form of the model thoroughly discuss its features and solutions to the problems introduced due to measurement error. We discuss higher-dimensional and more advanced forms of the model and give a brief numerical illustration.

PurposeThe aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials.MethodsProspective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p4 comorbidities (OR 4.5; CI 1.7–11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3–46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1–999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9–>1000), concern about care if not on trial (OR12.1; CI 2.1–71.4), pressure to enroll (OR .27; CI 0.12–.64), caregiving without pay (OR 0.13; CI .02–.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6–8.4), and trial would not be time consuming (OR 3.3; CI 1.3–8.1).ConclusionsTrial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials.

Descriptions of significant associations found from a logistic regression analysis typically are based on adjusted odds ratios. Unfortunately, odds ratios provide no information about the prevalence of response. In this paper, we justify and recommend using standardized risks, i.e., standardized probabilities, which do provide information about prevalence, in addition to adjusted odds ratios, for pairwise comparisons of the levels of a significant factor. We illustrate the advantages of generally reporting standardized risk estimates, in the context of assessing the effect of blood lead levels during the preschool years on occurrence of academic problems in kindergarten. Results are more meaningfully interpreted when accompanied by standardized risk estimates.

Chromosomal instability, manifesting as copy number alterations (CNAs), is characteristic of pancreatic adenocarcinoma. We used bacterial artificial chromosome (BAC) array-based comparative genomic hybridization (aCGH) to examine the pancreatic adenocarcinoma genome for submicroscopic amplifications and deletions. Profiles of 33 samples (17 first-passage xenografts and 16 cell lines) identified numerous chromosomal regions with CNAs, including losses at 1p36.33 approximately p34.3, 1p13.3 approximately p13.2, 3p26, 3p25.2 approximately p22.3, 3p22.1 approximately p14.1, 4q28.3, 4q31, 4q35.1, 5q14.3, 6p, 6q, 8p23.3 approximately p12, 9p, 9q22.32 approximately q31.1, 13q33.2, 15q11.2, 16p13.3, 17p, 18q11.21 approximately q23 , 19p13.3 approximately p13.12, 19q13.2, 21p, 21q, and 22p, 22q and gains at 7p21.1 approximately p11.2, 7q31.32, 7q33, 8q11.1 approximately q24, 11p13, 14q22.2, 20p12.2, and 20q11.23 approximately q13.33. Novel regions containing CNAs were identified and refined by combining the increased resolution of our BAC CGH array with a statistical algorithm developed for assigning significance values to altered BACs across samples. A subset of array-based CNAs was validated using polymerase chain reaction-based techniques, immunohistochemistry and fluorescence in situ hybridization. BAC aCGH proved to be a powerful genome-wide strategy to identify molecular alterations in pancreatic cancer and to distinguish differences between cell line and xenograft aberration profiles. These findings should greatly facilitate further research in understanding the pathogenesis of this lethal disease, and could lead to the identification of novel therapeutic targets and biomarkers for early detection.

Objective Patency rates for autogenous accesses are presumed to be better than for polytetrafluoroethylene (PTFE) accesses, although the strength of the supporting evidence is limited. We undertook this study to test the hypothesis that patency rates for upper extremity autogenous hemodialysis arteriovenous accesses in adults are superior to those for PTFE counterparts. Methods A systematic review of relevant literature and meta-analysis of the patency data were performed. Studies were considered acceptable if patency data were reported by either life table or Kaplan-Meier method, including number of patients at risk. Results The thirty-four studies that satisfied the inclusion criteria were composed predominantly of case series or nonrandomized controlled studies; no randomized, controlled studies comparing autogenous and PTFE accesses were included. The primary patency rate for autogenous accesses was 72% (95% confidence interval [CI], 70%-74%) at 6 months and 51% (95% CI, 48%-53%) at 18 months, and the corresponding primary patency rate for PTFE accesses was 58% (95% CI, 56%-61%) and 33% (95% CI, 31%-36%), respectively. The secondary patency rate for autogenous accesses was 86% (95% CI, 84%-88%) at 6 months and 77% (95% CI, 74%-79%) at 18 months, and the corresponding secondary patency rate for PTFE accesses was 76% (95% CI, 73%-79%) and 55% (95% CI, 51%-59%), respectively. Conclusions The patency rate for autogenous upper extremity arteriovenous hemodialysis accesses in adults is superior to that for PTFE counterparts, although the overall quality of the studies in the meta-analysis was less than ideal. Randomized, controlled studies to further examine the differences in outcome between these two access types are necessary.

Objectives: To develop a risk-assessment screening tool for very low birth weight (VLBW) and to compare our empirically derived tool to the nonempirically derived screening tool used by the State of Florida. Methods: Birth records from the State of Florida Vital Statistics between 04/01/92 and 12/07/94 were matched with State Healthy Start prenatal records, reported from 04/01/92 through 03/31/94. Known and additional potentially important risk factors were identified from both sources. Generalized Linear Modeling techniques were used to estimate associations between risk factors and VLBW. A risk assessment system was then developed using the estimated model. The resulting screening test was compared with the one used by the Florida State Department of Health in terms of sensitivity and specificity on an independent validation sample. Results: The proposed screening tool had comparable specificity to the Healthy Start screening tool but significantly better sensitivity. Both instruments are simple and easy to implement. Conclusions: Identification of women at high risk for VLBW would be improved using the model-based screening tool developed in this paper. Public health policy makers should use statistical methods in addition to expert opinion to improve existing risk assessment methods. The actual value of an improved screening instrument is dependent on the availability of effective intervention programs.

To assess the frequency of cytogenetic abnormalities in children with autism spectrum disorders (ASDs), routine G-banded cytogenetic analyses and FISH studies to rule out 15q11.2 and 17p11.2 duplications were performed on 49 children with ASDs. Blood samples were further studied using a complete set of subtelomeric FISH probes. Routine chromosome study showed that one child had a small duplication of chromosome 5: 46,XY,dup(5)(p?14.2p?15.1). Another child had an interstitial duplication of the Prader-Willi and Angelman syndrome critical region of chromosome 15, detected by FISH analysis. The detection of these two cases underscores the importance of obtaining routine chromosome and 15q11-q13 FISH analyses in children with ASDs. No instance of 17p11.2 duplication was observed. Subtelomeric analysis did not reveal abnormalities in any of the subjects.

We consider the problem of record linkage in the situation where we have only non-unique identifiers, like names, sex, race etc., as common identifiers in databases to be linked. For such situations much work on probabilistic methods of record linkage can be found in the statistical literature. However, although many groups undoubtedly still use deterministic procedures, not much literature is available on deterministic strategies. Furthermore, there appears to exist almost no documentation on the comparison of results for the two strategies. In this work we compare a stepwise deterministic linkage strategy with a probabilistic strategy, as implemented in AUTOMATCH, for a situation in which the truth is known. The comparison was carried out on a linkage between medical records from the Regional Perinatal Intensive Care Centers database and educational records from the Florida Department of Education. Social security numbers, available in both databases, were used to decide the true status of each record pair after matching. Match rates and error rates for the two strategies are compared and a discussion of their similarities and differences, strengths and weaknesses is presented.

For confidentiality reasons, US federal death certificate data are incomplete with regards to the dates of birth and death for the decedents, making calculation of total lifetime of a decedent impossible and thus estimation of mortality incidence difficult. This paper proposes the use of natality data and an imputation-based method to estimate age-specific mortality incidence rates in the face of this missing information. By utilizing previously determined probabilities of birth, a birth date and death date are imputed for every decedent in the dataset. Thus, the birth cohort of each individual is imputed, and the total on-study time can be calculated. This idea is implemented in two approaches for estimation of mortality incidence rates. The first is an extension of a person-time approach, while the second is an extension of a life table approach. Monte Carlo simulations showed that both approaches perform well in comparison to the ideal complete data methods, but that the person-time method is preferred. An application to Tay-Sachs disease is demonstrated. It is concluded that the imputation methods proposed provide valid estimates of the incidence of death from death certificate data without the need for additional assumptions under which usual mortality rates provide valid estimates.

© 2014 John Wiley & Sons, Ltd. Multiple indicators, multiple causes (MIMIC) models are often employed by researchers studying the effects of an unobservable latent variable on a set of outcomes, when causes of the latent variable are observed. There are times, however, when the causes of the latent variable are not observed because measurements of the causal variable are contaminated by measurement error. The objectives of this paper are as follows: (i) to develop a novel model by extending the classical linear MIMIC model to allow both Berkson and classical measurement errors, defining the MIMIC measurement error (MIMIC ME) model; (ii) to develop likelihood-based estimation methods for the MIMIC ME model; and (iii) to apply the newly defined MIMIC ME model to atomic bomb survivor data to study the impact of dyslipidemia and radiation dose on the physical manifestations of dyslipidemia. As a by-product of our work, we also obtain a data-driven estimate of the variance of the classical measurement error associated with an estimate of the amount of radiation dose received by atomic bomb survivors at the time of their exposure.

This review addresses difficulties arising in estimating epidemiological parameters of leukodystrophies and lysosomal storage disorders, with special focus on Krabbe disease. Although multiple epidemiological studies of Krabbe disease have been published, these studies are difficult to reconcile since they have used different study populations and varying methods of calculation. Confusion exists regarding which epidemiological parameters have been estimated; the current review shows that most previous estimates can be properly interpreted as lifetime risk at birth. One of the most common estimation methods is shown to be inaccurate, while two other methods are shown to be approximately accurate. Based on the results of the current paper, recommendations are made that are expected to improve the quality of future studies of Krabbe disease. It is anticipated that these recommendations will be applicable to epidemiological studies of other lysosomal storage disorders, as well as any other rare diseases diagnosed with enzymatic screening.

This study sought to determine whether galactocerebrosidase activity is predictive of Krabbe onset age, or of survival from onset when controlling for age at onset of signs. We analyzed data on 55 symptomatic patients from the Hunter James Kelly Research Institute's World-Wide Registry. They were tested for galactocerebrosidase activity at Jefferson Medical College (Philadelphia, PA), using survival models in a path model context. Higher galactocerebrosidase activity was predictive of later symptom onset times ( P = 0.0011), but did not predict survival after symptom onset ( P = 0.9064) when controlling for the logarithm of age at onset. No child with early infantile (aged 0-6 months) phenotype demonstrated galactocerebrosidase activity >0.1 nmol/hour/mg protein. Survival times within a given phenotype did not vary with galactocerebrosidase activity. Although low galactocerebrosidase activity does not predict phenotype, higher activity in the abnormal range (>0.1 nmol/hour/mg protein in this sample) was not identified in the early infantile variant. Galactocerebrosidase activity may be important to consider when predicting phenotype in the newborn screening population. Our findings provide empiric evidence that the upper end (0.15 nmol/hour/mg protein) of the high-risk galactocerebrosidase group in the New York State newborn screening program is conservatively appropriate.

Based on the Atomic Bomb Casualty Commission/Radiation Effects Research Foundation series of over 5,000 autopsies, we examined death certificate accuracy for 12 disease categories and assessed the effect of potential modifying factors on agreement and accuracy. The overall percentage agreement between death certificate and autopsy diagnoses was only 52.5%. Although neoplasms had the highest detection rate, almost 25% of cancers diagnosed at autopsy were nevertheless missed on death certificates. Confirmation and detection rates were above 70% for neoplasms and external causes of death only. Confirmation rates were between 50 and 70% for infectious diseases and heart and other vascular diseases. Detection rates reached a similar level for infectious, cerebrovascular, and digestive diseases. Specificity rates were above 90% for all except the cerebrovascular disease category. Overall agreement decreased with increasing age at death and was worse for deaths occurring outside of hospital. There was some suggestion that agreement improved over time, but no indication that radiation dose, sex, city of residence, or inclusion in a biennial clinical examination program influenced agreement. Since the inaccuracy of death certificate diagnoses can have major implications for health research and planning, it is important to be aware that their accuracy is low and that it can vary widely depending on cause, age and place of death.

Russell W Bessette1, Randy L Carter2,3 1Department of Health Sciences, Institute for Healthcare Informatics, 2Department of Biostatistics, 3Population Health Observatory, University at Buffalo, State University of New York, Buffalo, NY, USA Background: Despite significant investments of federal and state dollars to transition patient medical records to an all-electronic system, a chasm still exists between health care quality and payment for it. A major reason for this gap is the difficulty in evaluating health care outcomes based on claims data. Since both payers and patients may not appreciate how illness complexity impacts treatment outcomes, it is difficult to determine fair provider compensation. Objectives: Chronic kidney disease (CKD) typifies these problems and is often associated with comorbidities that impact cost, health, and work productivity. Thus, the objective of this study was to evaluate an illness complexity score (ICS) based on a linear regression of select blood values that might assist in predicting average monthly reimbursements in CKD patients. A second objective was to compare the results of this ICS prediction to results obtained by prediction of average monthly reimbursement using CKD stage. A third objective was to analyze the relationship between the change in ICS, estimated glomerular filtration rate (eGFR), and CKD stage over time to average monthly reimbursement. Methods: We calculated parsimonious values for select variables associated with CKD patients and compared the ICS to ordinal staging of renal disease. Data from 177 de-identified patients over 13 months was collected, which included 15 blood chemistry observations along with complete claims data for all medical expenses. To test for the relationship between average blood chemistry values, stages of CKD, age, and average monthly reimbursement, we modeled an association through a linear regression function of age, eGFR, and the Z-scores calculated from average monthly values of phosphorus, parathyroid hormone, glucose, hemoglobin, bicarbonate, albumin, creatinine, blood urea nitrogen, potassium, calcium, sodium, alkaline phosphatase, alanine aminotransferase, and white blood cells. Results: The results of our study demonstrated that the association between average ICS values throughout the entire study period predicted average monthly reimbursements with an R2 value of 0.41. Comparing that value to the association between the average CKD stage and average monthly reimbursement demonstrated an R2 value of 0.08. Thus, ICS offers five times greater sensitivity over CKD staging as a measure of illness complexity. Conclusion: Sorting the patient population by changes in CKD stage or ICS over the entire study period revealed significant differences between the two scoring methods. Groups scored by ICS demonstrated greater sensitivity by capturing dysfunction in other organ systems and had a better association with reimbursement than groups scored by CKD staging. Keywords: chronic kidney disease, illness complexity score, reimbursement, disease severity

Leukodystrophies (LD) and lysosomal storage disorders (LSD) have generated increased interest recently as targets for newborn screening programs. Accurate epidemiological benchmarks are needed in the U.S. Age-specific mortality rates were estimated for Krabbe disease (KD) and nine related disorders. U.S. mortality records with E75.2 cause of death code during 1999-2004 were collected from 11 open record states. All E75.2 deaths in the United States were distributed into specific disease type based on proportions observed in these states. Yearly population sizes were obtained from the CDC and averaged. Mortality rates (per million individuals per year) by age group for the specific diseases were (for

New York State began screening for Krabbe disease in 2006 to identify infants with Krabbe disease before symptom onset. Because neither galactocerebrosidase activity nor most genotypes reliably predict phenotype, the World Wide Registry was developed to determine whether other clinical/neurodiagnostic data could predict early infantile Krabbe disease in the newborn screening population. Data on disease course, galactocerebrosidase activity, DNA mutations, and initial neurodiagnostic studies in 67 symptomatic children with early infantile Krabbe disease were obtained from parent questionnaires and medical records. Initial signs included crying/irritability, cortical fisting, and poor head control. Galactocerebrosidase activity was uniformly low. Eight of 17 manifested novel mutations. Ninety-two percent (n = 25) exhibited elevated cerebrospinal fluid protein; 76% (n = 42) demonstrated abnormal magnetic resonance images; 67% (n = 15) exhibited abnormal computed tomography findings; 43% (n = 28) produced abnormal electroencephalogram findings; 100% (n = 5) demonstrated abnormal nerve conduction velocities; 83% (n = 6) produced abnormal brainstem evoked responses; and 50% (n = 6) exhibited abnormal visual evoked responses. One, 2, and 3 year survivals were 60%, 26%, and 14%, respectively. Although most symptomatic patients with the early infantile phenotype manifested abnormal cerebrospinal fluid protein, magnetic resonance imaging, brainstem evoked responses, and nerve conduction velocities, studies of affected children may be normal. Other biomarkers are needed to predict phenotype in the newborn screening population.

Studies of developmental outcome of neonatal intensive care unit graduates have generally been limited to the first 2 to 3 years of life, with outcome determined by psychometric tests. This study followed neonatal intensive care unit graduates born 1975 through 1983 (n = 457) into the public school system and compared their educational outcomes with those of newborn nursery graduates (n = 656). Outcomes were evaluated by placement in four academic categories: regular classroom, academic problems, speech/language impairment, and major impairment. Educational outcomes for children of both groups were essentially the same. Their placement in the four academic categories were equally affected by nonmedical variables, primarily income (below/above poverty level), race, and sex. Seventy percent of poverty-level children were in one of the three problem categories, compared with 40% of children above poverty level. Neither neonatal intensive care unit treatment nor low birth weight were major predictors of educational outcome. The only clear-cut neonatal intensive care unit effect occurred among children born with sensory or physical impairments. Therefore, in order to reduce poor educational outcomes, follow-up and intervention programs should be targeted primarily to children with diagnosable handicaps and from minority, low-income families.

In many medical studies, longitudinal data are collected on each of a sample of patients. The objectives of such studies often are: to estimate and test bivariate or multivariate relationships within each of several groups of patients from these repeated measures data; to compare these relationships among groups; and to test for the effects of baseline covariates on the relationships. This paper illustrates the use of statistical methods for growth curve analysis recently proposed by Vonesh and Carter for achieving these goals by relating a measure of preschool cognitive development to age in four race by sex groups of low-birth-weight infants. Significant declines in Bayley's Mental Development Index (MDI) with increasing age were found in all groups. Birth-weight did not significantly influence the rate of decline but did influence the overall level of performance. Even so, in the group most comparable to Bayley's normative population, predicted MDI was near the norm even for extremely low-birth-weight infants (that is, 1000 grams). Although there is some risk of mental deficit associated with prematurity, eventual developmental delays in low-birth-weight infants frequently are acquired with age. The rate of decline in MDI was significantly associated with race and mother's education. Assumptions required for the valid application of these methods are discussed and tested in the setting of this applied problem. The assumptions appeared valid in this application. We conclude with a brief discussion of available alternatives when the assumptions are violated and point to areas for future research.

Doel van het huidige onderzoek was vast te stellen of patienten met recidiverende lage-rugpijn over meerdere dagen een ander fluctuatiepatroon in hun gemoedstoestand vertonen dan vergelijkbare gezonde controlepersonen en of deze gemoedstoestanden verband houden met het optreden van pijn en/of de ernst van de pijn, met toepassing van een prospectieve opzet. De te beantwoorden vraagstellingen waren of gemoedstoestanden voorafgaand aan een pijnperiode verband houden met die periode of dat gemoedstoestand samenhangt met pijn als secundaire reactie. Overeenkomstig werd de relatie tussen de gemoedstoestand, die voorafgaand aan, gedurende of volgend op de pijn werd waargenomen, en de ernst van de ondervonden pijn onderzocht.

Improving medical treatment of extremely low-birth-weight infants over the last 20 to 30 years resulted in increased survival rates. The developmental sequela of salvaged infants is of great interest to perinatologists. The primary purposes of the current study were to assess the effect of birth weight (BW) on developmental delay or disability (DDD) in the first three years of life and determine whether there is a BW threshold below which all infants should be evaluated to determine if intervention services for children with DDD should be received. Three statewide databases were merged: 1998 Birth Vital Statistics; 1997-1998 Medicaid eligibility files; and 1998-2001 Children's Medical Services' Early Intervention Program (CMS-EIP) data. Infants who died within the first year of life and plural births were excluded. The final dataset consisted of 170,874 records. A child was determined to have a DDD if a developmental delay, or an established condition, such as sensory impairment, genetic, metabolic, neurological, or severe attachment disorders, was diagnosed through a multidisciplinary evaluation. Logistic regression models were used to relate BW to DDD, controlling for sociodemographic, behavioral, and perinatal variables. Adjusted odds ratios (OR) were calculated to describe the effects of BW on DDD. There was a significant effect of BW on DDD (Adjusted OR &equals 97.50, 40.01, 15.84, 3.29, 1.39, 1.00, 1.52 for BW categories 450-749, 750-999, 1000-1499, 1500- 2499, 2500-2999, 3000-4749, 4750-6050 g, respectively). In these categories, 70%, 56%, 36%, 11%, 4%, 3%, and 6% of surviving singleton infants, respectively, suffered a DDD in their first 3 years of life. Four medical, five sociodemographic, and two behavioral factors were significant in addition to BW. An equation for predicting the probability of DDD given these factors was obtained, and its use exemplified. BW is strongly associated with DDD. Over 60% of infants weighing < 1000 g and nearly half (46%) of those weighing < 1500 g at birth are diagnosed with a DDD before 3 years of age. The probability of DDD for a specific infant also varies by sociodemographic, other perinatal, and behavioral factors. The results of this paper suggest that all surviving infants of BW < 1000 g, and perhaps < 1500 g, should be automatically referred for evaluation.

Context: Of the approximately 900,000 children who were determined to be victims of abuse or neglect by US child protective services in 2002, the birth-to-3 age group had the highest rate of victimization (1.6%) and children younger than 1 accounted for the largest percentage of victims (9.6%). Objective: To identify perinatal and sociodemographic risk factors associated with maltreatment of infants up to 1 year of age. Design and Setting: Observational cohort study. Participants: 189,055 children born in 1996 in Florida. Main Outcome Measure: Infant maltreatment, defined as a verified report of abuse, neglect, or threatened harm that occurred between day 3 of life and 1 year. Results: 1,602 children (.85%) of the 1996 birth cohort had verified instances of maltreatment by age 1. Of 15 perinatal and sociodemographic variables studied, 11 were found to be significantly related to infant maltreatment. Five factors had adjusted relative risks (RR) of two or greater: Mother smoked during pregnancy (RR 2.8); more than two siblings (RR 2.7); Medicaid beneficiary (RR 2.1); unmarried marital status (RR 2.0); low birth weight infant (RR 2.0). Infants who had four of these five risk factors had a maltreatment rate seven times higher than the population average. Conclusions: Data on nearly all risk factors found to be significantly associated with infant maltreatment are available on the birth certificate. Such information can be incorporated into a population-based risk-assessment tool that could identify subpopulations at highest risk for infant maltreatment. Because resources are limited, these groups should be given priority for enrollment in child abuse prevention programs.

To develop a risk-assessment screening tool for very low birth weight (VLBW) and to compare our empirically derived tool to the nonempirically derived screening tool used by the State of Florida.Birth records from the State of Florida Vital Statistics between 04/01/92 and 12/07/94 were matched with State Healthy Start prenatal records, reported from 04/01/92 through 03/31/94. Known and additional potentially important risk factors were identified from both sources. Generalized Linear Modeling techniques were used to estimate associations between risk factors and VLBW. A risk assessment system was then developed using the estimated model. The resulting screening test was compared with the one used by the Florida State Department of Health in terms of sensitivity and specificity on an independent validation sample.The proposed screening tool had comparable specificity to the Healthy Start screening tool but significantly better sensitivity. Both instruments are simple and easy to implement.Identification of women at high risk for VLBW would be improved using the model-based screening tool developed in this paper. Public health policy makers should use statistical methods in addition to expert opinion to improve existing risk assessment methods. The actual value of an improved screening instrument is dependent on the availability of effective intervention programs.

Teenage pregnancies have become a public health issue because of their observed negative effects on perinatal outcomes and long-term morbidity. The association of young maternal age and long-term morbidity is usually confounded, however, by the high prevalence of poverty, low level of education, and single marital status among teenage mothers. The authors assess the independent effect of teenage pregnancy on educational disabilities and educational problems in a total population of children who entered kindergarten in Florida in 1992--1994 and investigate how controlling for potentially confounding factors affects the relation between teenage pregnancies and poor outcome. When no other factors are taken into account, children of teenage mothers have significantly higher odds of placement in certain special education classes and significantly higher occurrence of milder education problems, but when maternal education, marital status, poverty level, and race are controlled, the detrimental effects disappear and even some protective effects are observed. Hence, the increased risk for educational problems and disabilities among children of teenage mothers is attributed not to the effect of young age but to the confounding influences of associated sociodemographic factors. In contrast to teen age, older maternal age has an adverse effect on a child's educational outcome regardless of whether other factors are controlled for or not.

Objectives: The purpose of this study was to determine outcome and identify predictors of death after thoracoabdominal aortic aneurysm (TAA) repair, renal artery bypass (RAB), and revascularization for chronic mesenteric ischemia (CMI). Patients and Methods: In this retrospective analysis, data were obtained from the Nationwide Inpatient Sample, a 20% all-payer stratified sample of hospitals in the United States during 1993 to 1997. Patients were identified by the presence of a diagnostic or procedure code from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The main outcomes we examined were death, ICD-9-CM –based complications, length of stay, hospital charges, and disposition. A multivariate model was constructed to predict death. Results: A total of 2934 patients were identified (TAA, 540; RAB, 2058; CMI, 336) in the database. The mean age was comparable (TAA, 69 ± 9 years; RAB, 66 ± 12 years; CMI, 66 ± 11 years), but the breakdown between the sexes varied by procedure (male: TAA, 53%; RAB, 55%; CMI, 24%). The mortality rate (TAA, 20.3%; RAB, 7.1%; CMI, 14.7%), complication rate (TAA, 62.2%; RAB, 37.4%; CMI, 44.6%), and the percentage of patients discharged to another institution (TAA, 21.2%; RAB, 9.3%; CMI, 12.0%) were clinically significant for all procedures. The mortality rate for RAB was greater when performed concomitant with an aortic reconstruction (4.4% vs 8.3%). All three procedures were resource intensive as reflected by the median length of stay (TAA, 14 days; RAB, 9 days; CMI, 14 days) and median hospital charges (TAA, $64,493; RAB, $36,830; CMI, $47,390). The multivariate model identified several variables for each procedure that had an impact on the predicted mortality rate (TAA, 14%-76%; RAB, < 1%-46%; CMI, < 2%-87%). Conclusions: The operative mortality rates across the United States for patients undergoing TAA repair and RAB are greater than commonly reported in the literature and mandate reexamining the treatment strategies for these complex vascular problems. (J Vasc Surg 2001;34:54-61.)

Objective. To assess the relative effects and the impact of perinatal and sociodemographic risk factors on long-term morbidity within a total birth population in Florida. Methods. School records for 339 171 children entering kindergarten in Florida public schools in the 1992–1993, 1993–1994, or 1994–1995 academic years were matched with Florida birth records from 1985 to 1990. Effects on long-term morbidity were assessed through a multivariate analysis of an educational outcome variable, defined as placement into 9 mutually exclusive categories in kindergarten. Of those categories, 7 were special education (SE) classifications determined by statewide standardized eligibility criteria, 1 was academic problems, and the reference category was regular classroom. Generalized logistic regression was used to simultaneously estimate the odds of placement in SE and academic problems. The impact of all risk factors was assessed via estimated attributable excess/deficit numbers, based on the multivariate analysis. Results. Educational outcome was significantly influenced by both perinatal and sociodemographic factors. Perinatal factors had greater adverse effects on the most severe SE types, with birth weight 10 times greater than that of very low birth weight, presence of a congenital anomaly, or prenatal care. Conclusions. Results are consistent with the hypothesis that adverse perinatal conditions result in severe educational disabilities, whereas less severe outcomes are influenced by sociodemographic factors. Overall, sociodemographic factors have a greater total impact on adverse educational outcomes than perinatal factors.

Objective. To determine the relationship between perinatal and sociodemographic factors in low birth weight and sick infants hospitalized at regional neonatal intensive care units (NICUs) and subsequent educational disabilities.Method. NICU graduates born between 1980 and 1987 at nine statewide regionalized level III centers were located in Florida elementary schools (kindergarten through third grade) during academic year 1992–1993 (n = 9943). Educational disability was operationalized as placement into eight mutually exclusive types of special education (SE) classifications determined by statewide standardized eligibility criteria: physically impaired, sensory impaired (SI), profoundly mentally handicapped, trainable mentally handicapped, educable mentally handicapped, specific learning disabilities, emotionally handicapped, and speech and language impaired (SLI). Logistic regression was used to estimate the odds of placement in SE for selected perinatal and sociodemographic variables.Results. Placement into SE ranged from .8% for SI to 9.9% for SLI. Placement was related to four perinatal factors (birth weight, transport, medical conditions [congenital anomalies, seizures or intraventricular hemorrhage] and ventilation), and five sociodemographic factors (child's sex, mother's marital status, mother's race, mother's educational level, and family income). Perinatal factors primarily were associated with placement in physically impaired, SI, profoundly mentally handicapped, and trainable mentally handicapped. Perinatal and sociodemographic factors both were associated with placement in educable mentally handicapped and specific learning disabilities whereas sociodemographic factors primarily were associated with placement in emotionally handicapped and SLI.Conclusions. Educational disabilities of NICU graduates are influenced differently by perinatal and sociodemographic variables. Researchers must take into account both sets of these variables to ascertain the long-term risk of educational disability for NICU graduates. Birth weight alone should not be used to assess NICU morbidity outcomes.

Background Chronic kidney disease is associated with disruption of the endocrine system that distorts the balance between calcitriol, calcium, phosphate and parathyroid hormone in the calcium regulation system. This can lead to calcification of the arterial tree and increased risk of cardiovascular disease and death. In this study we develop a health metric, based on biomarkers involved in the calcium regulation system, for use in identifying patients at high risk for future high-cost complications. Methods This study is a retrospective observational study involving a secondary analysis of data from the kidney disease registry of a regional managed care organization. Chronic kidney disease patients in the registry from November 2007 through November 2011 with a complete set of observations of estimated glomerular filtration rate, calcitriol, albumin, free calcium, phosphate, and parathyroid hormone were included in the study (n = 284). Weibull regression model was used to identify the most significant lab tests in predicting “waiting time to hospitalization”. A multivariate linear path model was then constructed to investigate direct and indirect effects of the biomarkers on this outcome. Results The results showed negative significant direct effects of phosphate and parathyroid hormone on “waiting time to hospitalization”. Base on this result, the risk of hospitalization increases 16.8% for each 0.55 mg/dl increase in phosphate level and 13.5% for each 0.467 increase in the natural logarithm of parathyroid hormone. Positive indirect effects of calcitriol surrogate (calcidiol), free calcium, albumin and estimated glomerular filtration rate were observed but were relatively small in magnitude. Conclusion Variables involved in the calcium regulation system should be included in future efforts to develop a quality of care index for Chronic Kidney disease patients.