Challenging Dogma by Skipping the Emergency Department Thoracotomy: A Propensity Score Matched Analysis of the Trauma Quality Improvement Database.

INTRODUCTION: Survival following emergency department thoracotomy (EDT) for patients in extremis is poor. Whether intervention in the operating room instead of EDT in select patients could lead to improved outcomes is unknown. We hypothesized that patients who underwent intervention in the operating room would have improved outcomes compared to those who underwent EDT. METHODS: We conducted a retrospective review of the Trauma Quality Improvement Program database from 2017 to 2021. All adult patients who underwent EDT, operating room thoracotomy (ORT), or sternotomy as the first form of surgical intervention within 1 h of arrival were included. Of patients without prehospital cardiac arrest, propensity score matching was utilized to create three comparable groups. The primary outcome was survival. Secondary outcomes included time to procedure. RESULTS: There were 1865 EDT patients, 835 ORT patients, and 456 sternotomy patients who met the inclusion criteria. There were 349 EDT, 344 ORT, and 408 sternotomy patients in the matched analysis. On Cox multivariate regression, there was an increased risk of mortality with EDT versus sternotomy (HR 4.64, P < 0.0001), EDT versus ORT (HR 1.65, P < 0.0001), and ORT versus sternotomy (HR 2.81, P < 0.0001). Time to procedure was shorter with EDT versus sternotomy (22 min versus 34 min, P < 0.0001) and versus ORT (22 min versus 37 min, P < 0.0001). CONCLUSIONS: There was an association between sternotomy and ORT versus EDT and improved mortality. In select patients, operative approaches rather than the traditional EDT could be considered.

Trusted Information Sources About the COVID-19 Vaccine Vary in Underserved Communities.

The COVID-19 pandemic was one of the deadliest global public health events. In the United States, over 1.1 million individuals have died, and now COVID-19 is the third leading cause of death (CDC, 2023). Vaccine uptake has stalled among different demographics. Vaccine hesitancy, a delay in accepting or refusing vaccines, poses a significant challenge regardless of the availability of safe and effective COVID-19 vaccines. This study aimed to identify disparate COVID-19 vaccine uptake among individuals in Western New York. The primary objective was to identify the factors contributing to lower rates of COVID-19 vaccination within this population.Data were collected from 585 adults recruited from 20 Niagara and Erie Counties sites using a self-administered survey on vaccine hesitancy, vaccination status, and COVID-19-related characteristics. The survey included the adult Vaccine Hesitancy Scale (aVHS) and acquired information on demographic characteristics and COVID-19 impact, knowledge, and information sources. Data were analyzed using descriptive statistics, a chi-squared test, a Wilcoxon rank-sum test, and a logistic regression model.Findings suggest that unvaccinated participants (n = 35) were concerned about vaccine side effects (48.6%). For vaccinated/unboosted participants (n = 52), they (40.0%) reported clinical concerns. After adjusting for gender and age, healthcare provider guidance and family guidance remained significant predictors of vaccination status, while clinical research studies were significant predictors of booster status. Findings from this study suggest public health interventions that target vaccine education and facilitate well-informed decisions about COVID-19 vaccines lead to less vaccine hesitancy.

The ICD-9 to ICD-10 transition has not improved identification of rapidly progressing stage 3 and stage 4 chronic kidney disease patients: a diagnostic test study.

BACKGROUND: The International Classification of Diseases (ICD) coding system is the industry standard tool for billing, disease classification, and epidemiology purposes. Prior research has demonstrated ICD codes to have poor accuracy, particularly in relation to rapidly progressing chronic kidney disease (CKD) patients. In 2016, the ICD system moved to revision 10. This study examines subjects in a large insurer database to determine the accuracy of ICD-10 CKD-staging codes to diagnose patients rapidly progressing towards end-stage kidney disease (ESKD). PATIENTS AND METHODS: Serial observations of outpatient serum creatinine measurements from 2016 to 2021 of 315,903 patients were transformed to estimated glomerular filtration rate (eGFR) to identify CKD stage-3 and advanced patients diagnosed clinically (eGFR-CKD). CKD-staging codes from the same time period of 59,386 patients and used to identify stage-3 and advanced patients diagnosed by ICD-code (ICD-CKD). eGFR-CKD and ICD-CKD diagnostic accuracy was compared between a total of 334,610 patients. RESULTS: 5,618 patients qualified for the progression analysis; 72 were identified as eGFR rapid progressors; 718 had multiple codes to qualify as ICD rapid progressors. Sensitivity was 5.56%, with positive predictive value (PPV) 5.6%. 34,858 patients were diagnosed as eGFR-CKD stage-3 patients; 17,549 were also diagnosed as ICD-CKD stage-3 patients, for a sensitivity of 50.34%, with PPV of 58.71%. 4,069 patients reached eGFR-CKD stage-4 with 2,750 ICD-CKD stage-4 patients, giving a sensitivity of 67.58%, PPV of 42.43%. 959 patients reached eGFR-CKD stage-5 with 566 ICD-CKD stage-5 patients, giving a sensitivity of 59.02%, PPV of 35.85%. CONCLUSION: This research shows that recent ICD revisions have not improved identification of rapid progressors in diagnostic accuracy, although marked increases in sensitivity for stage-3 (50.34% vs. 24.68%), and PPV in stage-3 (58.71% vs. 40.08%), stage-4 (42.43% vs. 18.52%), and stage-5 (35.85% vs. 4.51%) were observed. However, sensitivity in stage-5 compares poorly (59.02% vs. 91.05%).

General Surgery Resident Operative Experiences in Solid Organ Injury: An Examination of Case Logs.

BACKGROUND: Non-operative management (NOM) of traumatic solid organ injury (SOI) has become commonplace. This paradigm shift, along with reduced resident work hours, has significantly impacted surgical residents' operative trauma experiences. We examined ongoing changes in residents' operative SOI experience since duty hour restriction implementation, and assessed whether missed operative experiences were gained elsewhere in the resident experience. METHODS: We examined data from American College of Graduate Medical Education case log reports from 2003 to 2018. We collected mean case volumes in the categories of non-operative trauma, trauma laparotomy, and splenic, hepatic, and pancreatic trauma operations; case volumes for comparable non-traumatic solid organ operations were also collected. Solid organ injury operative volumes were compared against non-traumatic cases, and change over time was analyzed. RESULTS: Over the study period, both trauma laparotomies and non-operative traumas increased significantly (P < .001). In contrast, operative volumes for splenic, hepatic, and pancreatic trauma all significantly decreased (P < .001; P = .014; P < .001, respectively). Non-traumatic spleen cases also significantly decreased (P < .001), but liver cases and distal pancreatectomies increased (P < .001; P = .017). Pancreaticoduodenectomies increased, albeit not to a significant degree (P = .052). CONCLUSIONS: Continuing increases in NOM of SOI correlate with declining resident experience with operative solid organ trauma. These decreases can adversely affect residents' technical skills and decision-making, although trends in specific non-traumatic areas may help to mitigate such losses. Further work should determine the impact of these trends on resident competence and autonomy.

A Roadmap for Potential Improvement of Newborn Screening for Inherited Metabolic Diseases Following Recent Developments and Successful Applications of Bivariate Normal Limits for Pre-Symptomatic Detection of MPS I, Pompe Disease, and Krabbe Disease.

The mucopolysaccharidoses (MPS), Pompe Disease (PD), and Krabbe disease (KD) are inherited conditions known as lysosomal storage disorders (LSDs) The resulting enzyme deficiencies give rise to progressive symptoms. The United States Department of Health and Human Services' Recommended Uniform Screening Panel (RUSP) suggests LSDs for inclusion in state universal newborn screening (NBS) programs and has identified screening deficiencies in MPS I, KD, and PD NBS programs. MPS I NBS programs utilize newborn dried blood spots and assay alpha L-iduronidase (IDUA) enzyme to screen for potential cases. Glycosaminoglycans (GAGs) offer potential as a confirmatory test. KD NBS programs utilize galactocerebrosidase (GaLC) as an initial test, with psychosine (PSY) activity increasingly used as a confirmatory test for predicting onset of Krabbe disease, though with an excessive false positive rate. PD is marked by a deficiency in acid α-glucosidase (GAA), causing increased glycogen, creatine (CRE), and other biomarkers. Bivariate normal limit (BVNL) methods have been applied to GaLC and PSY activity to produce a NBS tool for KD, and more recently, to IDUA and GAG activity to develop a NBS tool for MPS I. A BVNL tool based on GAA and CRE is in development for infantile PD diagnosis. Early infantile KD, MPS I, and PD cases were pre-symptomatically identified by BVNL-based NBS tools. This article reviews these developments, discusses how they address screening deficiencies identified by the RUSP and may improve NBS more generally.

Death rates in the U.S. due to Leukodystrophies with pediatric forms.

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.

Development of a newborn screening tool for mucopolysaccharidosis type I based on bivariate normal limits: Using glycosaminoglycan and alpha-L-iduronidase determinations on dried blood spots to predict symptoms.

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.

Can billing codes accurately identify rapidly progressing stage 3 and stage 4 chronic kidney disease patients: a diagnostic test study.

BACKGROUND: The International Classification of Diseases (ICD) coding system is the industry standard tool for billing, disease classification, and epidemiology purposes. However, ICD codes are often not assigned or incorrectly given, particularly among Chronic Kidney disease (CKD) patients. Our study evaluated the diagnostic accuracy of CKD-staging ICD codes among CKD patients from a large insurer database in identifying individuals rapidly progressing towards end-stage renal disease (ESRD). PATIENTS AND METHODS: Serial observations including outpatient serum creatinine measurements collected from 2007 through 2014 of 216,529 patients were examined. The progression of CKD using a serum creatinine based longitudinal mixed-model was contrasted with that documented by CKD-staging ICD codes. Rapid progressors, defined as those with yearly estimated glomerular filtration rate (eGFR) loss greater than 4 ml/min/1.73m2) were identified. The diagnosis of CKD using eGFR was also compared to diagnosis using a set of CKD related ICD codes. RESULTS: Of 10,927 clinically identified CKD patients qualifying for inclusion in the progression analysis, 323 were clinically identified as rapid progressors. CKD-staging ICD codes identified 83 of these, for a sensitivity of 25.7% with positive predictive value (PPV) of 13.74%, and specificity 95.09% with negative predictive value (NPV) of 97.68%. Of 28,762 laboratory-confirmed CKD patients, 9249 had a qualifying ICD code, for a sensitivity of 16% with PPV of 63.10%; Of 187,767 patients with laboratory-confirmed absence of CKD, 182,359 also did not have a qualifying ICD code, for a specificity of 97.12% with NPV of 90.33%. CONCLUSION: This study depicts the novel finding that ICD-codes display poor capacity to identify rapidly progressing CKD patients when compared to gold standard eGFR measures, and further demonstrates the limitations of coding in CKD diagnosis. This analysis further defines the limitations of ICD codes in addressing diagnosis of disease severity or disease progression for clinical or epidemiological purposes.

Survey of quality of life, phenotypic expression, and response to treatment in Krabbe leukodystrophy.

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.

The impact of systematic review of status 7 patients on the kidney transplant waitlist.

BACKGROUND: Increased morbidity and mortality are well documented in Status 7(inactive list) patients. Delays in transplantation secondary to prolonged periods on inactive status also negatively impacts transplant outcomes. We developed an effective system to reduce the proportion of status 7 patients on our kidney transplant waitlist. This can easily be reproduced by other transplant centers since concerns about Status 7 list size are commonplace. METHODS: Meetings of a dedicated status 7 focus group were undertaken biweekly beginning in April 2016, each lasting for 1 hour or less. The group was led by a transplant physician and comprised of members from all disciplines of the kidney transplant department. Individual patient barriers to activation were systematically evaluated and action plans were developed to overcome those. The formal meetings were supplemented by updates to an electronic database accessible to all members of the team. RESULTS: In the first 2 years of the program, we were able to activate and eventually transplant 18% of the formerly inactive patients. Forty percent of all inactive patients were removed from the waitlist due to one or more unsurmountable barriers. The median time patients stayed inactive on the waitlist was shortened from 1344 days at the start of this initiative to 581 days at the end. CONCLUSION: This strategy of systematic reevaluation of status 7 patients resulted in successful disposition of a substantial number of inactive patients. Further, waitlist time was reduced and transplantation expedited for the appropriate individuals. This approach could easily be adapted by other transplant centers with minimum utilization of resources.

A critical issue of using the variance of the total in the linearization method - In the context of unequal probability sampling.

Publicly available national survey data are useful for the evidence-based research to advance our understanding of important questions in the health and biomedical sciences. Appropriate variance estimation is a crucial step to evaluate the strength of evidence in the data analysis. In survey data analysis, the conventional linearization method for estimating the variance of a statistic of interest uses the variance estimator of the total based on linearized variables. We warn that this common practice may result in undesirable consequences such as susceptibility to data shift and severely inflated variance estimates, when unequal weights are incorporated into variance estimation. We propose to use the variance estimator of the mean (mean-approach) instead of the variance estimator of the total (total-approach). We show a superiority of the mean-approach through analytical investigations. A real data example (the National Comorbidity Survey Replication) and simulation-based studies strongly support our conclusion.

Development of a newborn screening tool based on bivariate normal limits: using psychosine and galactocerebrosidase determination on dried blood spots to predict Krabbe disease.

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.

Impact of Trauma Hospital Ransomware Attack on Surgical Residency Training.

BACKGROUND: A recent ransomware attack led to the shutdown of the electronic health information system (HIS) at our trauma center for 2 mo. We investigated its impact on residency training during the downtime. MATERIAL AND METHODS: General and orthopedic surgical residents who rotated at the hospital were invited to participate in a survey regarding their patient care and residency training experiences during the downtime. Attending surgeons from both the specialties were invited to participate in a semistructured interview regarding their attitude toward residency training during the downtime. RESULTS: Twenty-nine residents responded to the survey with a response rate of 78.4%. Residents acknowledged significant increases in face-to-face communication and decreases in use of online educational resources during the downtime (P < 0.01). Residents were significantly stressed by the dearth of online resources (P < 0.0001) and by paper-based orders and outpatient clinic (P < 0.05). A multivariate analysis demonstrated an inverse relationship between postgraduate year and stress from paper orders (P = 0.003). Attending surgeon's interviews revealed that they recognized residents' unpreparedness and strove harder to teach more effectively. CONCLUSIONS: Our study demonstrated that an unexpected shutdown of the hospital HIS imposed significant stress upon surgical residents providing trauma patient care and made attending surgeons take greater efforts to be more effective teachers. Residents who are digital natives lack adaptability to handle a paper-based workflow. With cyber security threats increasing in health care, preparedness should be included in the graduate medical education curriculum.

Progression of kidney disease in elderly stage 3 and 4 chronic kidney disease patients.

PURPOSE: The prevalence of chronic kidney disease (CKD) has been rising steadily in the elderly population. We studied the rate of progression of CKD in this population and the factors associated with progression of CKD to better identify patients who are likely to progress to ESRD. METHODS: This was an observational study including 4562 patients older than 65 years with two outpatient estimated glomerular filtration rates (eGFRs) of <60 ml/min/1.73 m2, at least 90 days apart with no intervening eGFR >60 ml/min/1.73 m2 (March 1, 2001, and March 31, 2008) at VA healthcare facilities. Patients with eGFR <15 ml/min/1.73 m2 were excluded. Annual rate of decline of eGFR was studied and categorized as <1 ml/min/1.73 m2, 1-4 ml/min/1.73 m2, and >4 ml/min/1.73 m2. RESULTS: Mean age of the study participants was 77.2 years. 24.3% were diabetics. 4.3% had proteinuria. In univariate comparison of different rates of progression, 54.2% patients had an annual rate of progression of <1 ml/min/1.73 m2. Multivariable mixed model analyses revealed that increasing age, body mass index, presence of cardiovascular disease, diabetes mellitus, and proteinuria were associated with significantly increased rate of progression of CKD. Serum albumin and hemoglobin level were inversely associated with progression of CKD. CONCLUSIONS: CKD progresses at a slower rate in the elderly population. We have identified risk factors associated with an increased risk of progression of CKD in the elderly. This may help to improve health care planning and resource utilization.

Can psychosine and galactocerebrosidase activity predict early-infantile Krabbe's disease presymptomatically?

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.

Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.

BACKGROUND: Acute interstitial nephritis secondary to proton pump inhibitors (PPIs) frequently goes undiagnosed due to its subacute clinical presentation, which may later present as chronic kidney disease (CKD). We investigated the association of PPI use with the development of CKD and death. METHODS: Two separate retrospective case-control study designs were employed with a prospective logistic regression analysis of data to evaluate the association of development of CKD and death with PPI use. The population included 99,269 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of the CKD outcome, 22,807 with preexisting CKD at the first observation in Veterans Affairs Health Care Upstate New York (VISN2) network data system were excluded. Data obtained included use of PPI (Yes/No), demographics, laboratory data, pre-PPI comorbidity variables. RESULTS: A total of 19,311/76,462 patients developed CKD. Of those who developed CKD 24.4 % were on PPI. Patients receiving PPI were less likely to have vascular disease, COPD, cancer and diabetes. Of the total of 99,269 patients analyzed for mortality outcome, 11,758 died. A prospective logistic analysis of case-control data showed higher odds for development of CKD (OR 1.10 95 % CI 1.05-1.16) and mortality (OR 1.76, 95 % CI 1.67-1.84) among patients taking PPIs versus those not on PPIs. CONCLUSIONS: Use of proton pump inhibitors is associated with increased risk of development of CKD and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications.

Mortality incidence estimation using federal death certificate and natality data with an application to Tay-Sachs disease.

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.

Does galactocerebrosidase activity predict Krabbe phenotype?

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.

Later onset phenotypes of Krabbe disease: results of the world-wide registry.

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.

Early infantile Krabbe disease: results of the World-Wide Krabbe Registry.

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.