Spinal muscular atrophy (SMA) was added to the HHS Secretary's Recommended Uniform Screening Panel for newborn screening (NBS) in 2018, enabling early diagnosis and treatment of impacted infants to prevent irreversible motor neuron damage. In anticipation of supporting SMA newborn screening, scientists at the U.S. Centers for Disease Control and Prevention (CDC) have worked towards building resources for public health laboratories in four phases since 2013. In Phase 1, CDC established a real-time PCR assay, which uses a locked nucleic acid probe to attain the needed specificity, to detect SMN1 exon 7. In Phase 2, we developed quality assurance dried blood spot materials made with transduced lymphoblast cell lines established from de-identified SMA patients, carriers, and unaffected donors. In 2021, CDC implemented Phase 3, a proficiency testing program, that now supports 115 NBS labs around the world. We are currently completing Phase 4, which includes the implementation of an external SMA quality control material program. Also, during this time, CDC has provided individual technical assistance to NBS programs and bench training to NBS scientists during our annual molecular workshop. These CDC-led activities have contributed to the rapid and full implementation of SMA screening in all 50 U.S. states as of February 2024.

BACKGROUND: Single-tier newborn screening (NBS) for CAH using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24-48 hours produces a high false-positive rate (FPR). 2nd tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multi-tier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the 1st tier 17OHP cutoff to minimize missed cases. METHODS: Created a Minnesota-specific CYP21A2 pathogenic variants panel; develop a rapid, high-throughput multiplex, allele-specific-primer-extension assay; perform 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based two-tier protocol and a molecular-based multi-tier NBS protocol, applied post-hoc. RESULTS: CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. Centers for Disease Control and Prevention (CDC) created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68,659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A three-tier protocol with a lower 1st-tier steroid cutoff, 2nd-tier 21-variant CYP21A2 panel and 3rd-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs and 3 TPs. CONCLUSIONS: Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.

Newborn screening is the practice of testing every newborn for certain harmful or potentially fatal conditions, such as hearing loss and certain genetic, endocrine, and metabolic disorders that typically are not otherwise apparent at birth. Newborn screening in the United States began in the 1960s. Universal newborn screening has become a well-established, state-based, public health system involving education, screening, diagnostic follow-up, treatment and management, and system monitoring and evaluation. Each year, >98% of approximately 4 million newborns in the United States are screened. Through early identification, newborn screening provides an opportunity for treatment and significant reductions in morbidity and mortality.

Mucopolysaccharidosis type II (MPS-II, Hunter syndrome, OMIM:30990) is a lysosomal storage disorder (LSD) that results in iduronate 2-sulphatase (I2S) enzyme deficiency. MPS-II was added to the Recommended Uniform Screening Panel (RUSP) in August 2022; thus, there is an increased demand for multiplexing I2S into existing LSD screening assays. After incubation with LSD synthetic substrates, extracts are cleaned using liquid-liquid extraction with ethyl acetate or protein precipitation using acetonitrile (ACN). We investigated cold-induced water ACN phase separation (CIPS) to improve the combination of 6-plex and I2S extracts to create a 7-plex assay, and compared it to room temperature ACN and ethyl acetate liquid-liquid extraction. The extracts were dried and resuspended in the mobile phase, and then analyzed using an optimized 1.9 min injection-to-injection liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS). The combination of ACN and CIPS improved the detection for I2S products without significant detriment to other analytes, which is attributable to a more complete coagulation and separation of heme, proteins, and extracted residual salts. Using CIPS for sample cleanup in dried blood spots (DBS) appears to represent a promising and straightforward way of achieving cleaner sample extracts in a new 7-plex LSD screening panel.

We read with interest the recent article by Kingsmore et al., who suggest that universal newborn rapid whole-genome sequencing is attractive for “comprehensive” newborn screening (NBS).1 Existing US NBS programs are based on mandated routine testing of newborns; evidence-based decision-making processes exist for this testing.2 Whether policy makers also consider routine rapid whole-genome sequencing of newborns to be warranted may depend on the resolution of a number of evidentiary, ethical, legal, social, and economic issues.3 Kingsmore et al. suggest that sequencing can complement existing public-health NBS programs but acknowledge the challenge of reconciling universal or near-universal genomic screening with informed parental consent and the allowable secondary use of genomic information.1

In newborn screening, false-negative results can be disastrous, leading to disability and death, while false-positive results contribute to parental anxiety and unnecessary follow-ups. Cutoffs are set conservatively to prevent missed cases for Pompe and MPS I, resulting in increased falsepositive results and lower positive predictive values. Harmonization has been proposed as a way to minimize false-negative and false-positive results and correct for method differences, so we harmonized enzyme activities for Pompe and MPS I across laboratories and testing methods (Tandem Mass Spectrometry (MS/MS) or Digital Microfluidics (DMF)). Participating states analyzed proofof- concept calibrators, blanks, and contrived specimens and reported enzyme activities, cutoffs, and other testing parameters to Tennessee. Regression and multiples of the median were used to harmonize the data. We observed varied cutoffs and results. Six of seven MS/MS labs reported enzyme activities for one specimen for MPS I marginally above their respective cutoffs with results classified as negative, whereas all DMF labs reported this specimen's enzyme activity below their respective cutoffs with results classified as positive. Reasonable agreement in enzyme activities and cutoffs was achieved with harmonization; however, harmonization does not change how a value would be reported as this is dependent on the placement of cutoffs.

BACKGROUND: Classical homocystinuria (HCU) results from deficient cystathionine β-synthase activity, causing elevated levels of Met and homocysteine (Hcy). Newborn screening (NBS) aims to identify HCU in pre-symptomatic newborns by assessing Met concentrations in first-tier screening. However, unlike Hcy, Met testing leads to a high number of false-positive and -negative results. Therefore, screening for Hcy directly in first-tier screening would be a better biomarker for use in NBS. METHODS: Dried blood spot (DBS) quality control and residual clinical specimens were used in analyses. Several reducing and maleimide reagents were investigated to aid in quantification of total Hcy (tHcy). The assay which was developed and validated was performed by flow injection analysis-tandem mass spectrometry (FIA-MS/MS). RESULTS: Interferents of tHcy measurement were identified, so selective derivatization of Hcy was employed. Using N-ethylmaleimide (NEM) to selectively derivatize Hcy allowed interferent-free quantification of tHcy by FIA-MS/MS in first-tier NBS. The combination of tris(2-carboxyethyl)phosphine (TCEP) and NEM yielded significantly less matrix effects compared to dithiothreitol (DTT) and NEM. Analysis of clinical specimens demonstrated that the method could distinguish between HCU-positive, presumptive normal newborns, and newborns receiving total parenteral nutrition. CONCLUSIONS: Here we present the first known validated method capable of screening tHcy in DBS during FIA-MS/S first-tier NBS.

First-tier MS-based newborn screening by flow injection analysis can have high presumptive positive rates, often due to isomeric/isobaric compounds or poor biomarker specificity. These presumptive positive samples can be analyzed by second-tier screening assays employing separations such as liquid chromatography-mass spectrometry (LC-MS/MS), which increases test specificity and drastically reduces false positive referrals. The ability to screen for multiple disorders in a single multiplexed test simplifies workflows and maximizes public health laboratories' resources. In this study, we developed and validated a highly multiplexed second-tier method for dried blood spots using a hydrophilic interaction liquid chromatography (HILIC) column coupled to an MS/MS system. The LC-MS/MS method was capable of simultaneously detecting second-tier biomarkers for maple syrup urine disease, homocystinuria, methylmalonic acidemia, propionic acidemia, glutaric acidemia type 1, glutaric acidemia type 2, guanidinoacetate methyltransferase deficiency, short-chain acyl-CoA dehydrogenase deficiency, adrenoleukodystrophy, and Pompe disease.

BACKGROUND: Most first-tier newborn screening (NBS) biomarkers are evaluated by a 2-min flow injection analysis coupled to tandem mass spectrometry (FIA-MS/MS) assay. The absence of separation prior to MS/MS analysis can lead to false positives and inconclusive results due to interferences by nominal isobars and isomers. Therefore, many presumptive positive specimens require confirmation by a higher specificity second-tier assay employing separations, which require additional time and resources prior to patient follow-up. METHODS: A 3.2-mm punch was taken from dried blood spot (DBS) specimens and extracted using a solution containing isotopically labeled internal standards for quantification. Analyses were carried out in positive mode using a commercially available microfluidic capillary electrophoresis (CE) system coupled to a high-resolution mass spectrometer (HRMS). RESULTS: The CE-HRMS platform quantified 35 first- and second-tier biomarkers from a single injection in <2-min acquisition time, thus, successfully multiplexing first- and second-tier NBS for over 20 disorders in a single DBS punch. The CE-HRMS platform resolved problematic isobars and isomers that affect first-tier FIA-MS/MS assay specificity, while achieving similar quantitative results and assay linearity. CONCLUSIONS: Our CE-HRMS assay is capable of multiplexing first- and second-tier NBS biomarkers into a single assay with an acquisition time of <2 min. Such an assay would reduce the volume of false positives and inconclusive specimens flagged for second-tier screening.

Newborn screening (NBS) laboratories cannot accurately compare mass spectrometry-derived results and cutoff values due to differences in testing methodologies. The objective of this study was to assess harmonization of laboratory proficiency test (PT) results using quality control (QC) data. Newborn Screening Quality Assurance Program (NSQAP) QC and PT data reported from 302 laboratories in 2019 were used to compare results among laboratories. QC materials were provided as dried blood spot cards which included a base pool and the base pool enriched with specific concentrations of metabolites in a linear range. QC data reported by laboratories were regressed on QC data reported by the Centers for Disease Control and Prevention (CDC), and laboratory's regression parameters were used to harmonize their PT result. In general, harmonization tended to reduce overall variation in PT data across laboratories. The metabolites glutarylcarnitine (C5DC), tyrosine, and phenylalanine were displayed to highlight inter- and intra-method variability in NBS results. Several limitations were identified using retrospective data for harmonization, and future studies will address these limitations to further assess feasibility of using NSQAP QC data to harmonize PT data. Harmonizing NBS data using common QC materials appears promising to aid result comparison between laboratories.

Newborn screening (NBS) identifies infants at risk for congenital disorders for which early intervention has been shown to improve outcomes (1). State public health programs are encouraged to screen for disorders on the national Recommended Uniform Screening Panel (RUSP), which increased from 29 disorders in 2005 to 35 in 2018.* The RUSP includes hearing loss (HL) and critical congenital heart defects, which can be detected through point-of-care screening, and 33 disorders detected through laboratory screening of dried blood spot (DBS) specimens. Numbers of cases for 33 disorders on the RUSP (32 DBS disorders and HL) reported by 50 U.S. state programs were tabulated. The three subtypes of sickle cell disease (SCD) listed as separate disorders on the RUSP (S,S disease; S,beta-thalassemia; and S,C disease) were combined for the current analysis, and the frequencies of the resulting disorders were calculated relative to annual births. During 2015-2017, the overall prevalence was 34.0 per 10,000 live births. Applying that frequency to 3,791,712 live births in 2018,(†) approximately 12,900 infants are expected to be identified each year with one of the disorders included in the study. The most prevalent disorder is HL (16.5 per 10,000), and the most prevalent DBS disorders are primary congenital hypothyroidism (CH) (6.0 per 10,000), SCD (4.9 per 10,000), and cystic fibrosis (CF) (1.8 per 10,000). Notable changes in prevalence for each of these disorders have occurred since the previous estimates based on 2006 births (2). The number of infants identified at a national level highlights the effect that NBS programs are having on infant health through early detection, intervention, and potential improved health, regardless of geographic, racial/ethnic, or socioeconomic differences.

An increasing number of newborn screening laboratories in the United States and abroad are moving towards incorporating next-generation sequencing technology, or NGS, into routine screening, particularly for cystic fibrosis. As more programs utilize this technology for both cystic fibrosis and beyond, it is critical to identify appropriate DNA extraction methods that can be used with dried blood spots that will result in consistent, high-quality sequencing results. To provide comprehensive quality assurance and technical assistance to newborn screening laboratories wishing to incorporate NGS assays, CDC's Newborn Screening and Molecular Biology Branch designed a study to evaluate the performance of nine commercial or laboratory-developed DNA extraction methods that range from a highly purified column extraction to a crude detergent-based no-wash boil prep. The DNA from these nine methods was used in two NGS library preparations that interrogate the CFTR gene. All DNA extraction methods including the cruder preps performed reasonably well with both library preps. One lower-concentration, older sample was excluded from one of the assay evaluations due to poor performance across all DNA extraction methods. When 84 samples, versus eight, were run on a flow cell, the DNA quality and quantity were more significant variables.

OBJECTIVE: To describe trajectories of functioning up to 5 years after traumatic brain injury (TBI) that required inpatient rehabilitation in the United States using individual growth curve models conditioned on factors associated with variability in functioning and independence over time. DESIGN: Secondary analysis of population-weighted data from a multicenter longitudinal cohort study. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: A total of 4624 individuals 16 years and older with a primary diagnosis of TBI. MAIN OUTCOME MEASURES: Ratings of global disability and supervision needs as reported by participants or proxy during follow-up telephone interviews at 1, 2, and 5 years postinjury. RESULTS: Many TBI survivors experience functional improvement through 1 and 2 years postinjury, followed by a decline in functioning and decreased independence by 5 years. However, there was considerable heterogeneity in outcomes across individuals. Factors such as older age, non-White race, lower preinjury productivity, public payer source, longer length of inpatient rehabilitation stay, and lower discharge functional status were found to negatively impact trajectories of change over time. CONCLUSIONS: These findings can inform the content, timing, and target recipients of interventions designed to maximize functional independence after TBI.

This study characterized life expectancy after traumatic brain injury (TBI). The TBI Model Systems (TBIMS) National Database (NDB) was weighted to represent those ≥16 years of age completing inpatient rehabilitation for TBI in the United States (US) between 2001 and 2010. Analyses included Standardized Mortality Ratios (SMRs), Cox regression, and life expectancy. The US mortality rates by age, sex, race, and cause of death for 2005 and 2010 were used for comparison purposes. Results indicated that a total of 1325 deaths occurred in the weighted cohort of 6913 individuals. Individuals with TBI were 2.23 times more likely to die than individuals of comparable age, sex, and race in the general population, with a reduced average life expectancy of 9 years. Independent risk factors for death were: older age, male gender, less-than-high school education, previously married at injury, not employed at injury, more recent year of injury, fall-related TBI, not discharged home after rehabilitation, less functional independence, and greater disability. Individuals with TBI were at greatest risk of death from seizures; accidental poisonings; sepsis; aspiration pneumonia; respiratory, mental/behavioral, or nervous system conditions; and other external causes of injury and poisoning, compared with individuals in the general population of similar age, gender, and race. This study confirms prior life expectancy study findings, and provides evidence that the TBIMS NDB is representative of the larger population of adults receiving inpatient rehabilitation for TBI in the US. There is an increased risk of death for individuals with TBI requiring inpatient rehabilitation.

Newborn screening is the largest genetic testing effort in the United States and is considered one of the ten great public health achievements during the first 10 years of the 21st century. For over 35 years, the Newborn Screening Quality Assurance Program (NSQAP) at the US Centers for Disease Control and Prevention has helped NBS laboratories ensure that their testing does not delay diagnosis, minimizes false-positive reports, and sustains high-quality testing performance. It is a multi-component program that provides comprehensive quality assurance services for dried blood spot testing. The NSQAP, the Biochemical Mass Spectrometry Laboratory (BMSL), the Molecular Quality Improvement Program (MQIP) and the Newborn Screening Translation Research Initiative (NSTRI), aid screening laboratories achieve technical proficiency and maintain confidence in their performance while processing large volumes of specimens daily. The accuracy of screening tests could be the difference between life and death for many babies; in other instances, identifying newborns with a disorder means that they can be treated and thus avoid life-long disability or severe cognitive impairment. Thousands of newborns and their families have benefited from reliable and accurate testing that has been accomplished by a network of screening laboratories and the NSQAP, BMSL, MQIP and NSTRI.

OBJECTIVE: To estimate the prevalence of unemployment and part-time employment in the United States for working-age individuals completing rehabilitation for a primary diagnosis of traumatic brain injury (TBI) between 2001 and 2010. DESIGN: Secondary data analysis. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients aged 16 to 60 years at injury who completed inpatient rehabilitation for TBI between 2001 and 2010. MAIN OUTCOME MEASURES: Unemployment; Part-time employment. RESULTS: The prevalence of unemployment for persons in the selected cohort was 60.4% at 2-year postinjury. Prevalence of unemployment at 2-year postinjury was significantly associated with the majority of categories of age group, race, gender, marital status, primary inpatient rehabilitation payment source, education, preinjury vocational status, length of stay, and Disability Rating Scale. The direction of association for the majority of these variables complement previous research in this area, with only Hispanic ethnicity and the FIM Cognitive subscale demonstrating disparate findings. For those employed at 2-year postinjury, the prevalence of part-time employment was 35.0%. The model of prevalence for part-time employment at 2-year postinjury was less robust, with significant relationships with some categorical components of age group, gender, marital status, primary payment source, preinjury vocational status, and Disability Rating Scale. CONCLUSIONS: The prevalence of unemployment for patients completing inpatient rehabilitation for TBI was substantial (60.4%). The majority of factors found to associate with 2 years' unemployment were complementary of previously published research; however, these were often smaller in magnitude than previous reports. The prevalence of part-time employment was also an issue for this cohort and included 35.0% of all employed individuals. In regard to the determination of factors associated with part-time employment, additional analyses that include more fine-grained factors associated with employment, including physical and psychosocial functioning, are recommended.

Tyrosinemia type I (TYR I) is caused by autosomal recessive fumarylacetoacetate hydrolase deficiency and is characterized by development of severe liver disease in infancy and neurologic crises. If left untreated, most patients die of liver failure in the first years of life. Intervention with medication is effective when initiated during the first month of life. This improvement in the treatment of TYR I patients influenced the decision to include TYR I in the US Secretary of the Department of Health and Human Services' (HHS) Recommended Uniform Screening Panel. However, while tyrosine is routinely measured in newborn screening (NBS) by tandem mass spectrometry (MS/MS), elevated tyrosine levels are not specific to TYR I. To improve the specificity of NBS for TYR I, several assays were developed to measure succinylacetone (SUAC) in dried blood spots (DBS). SUAC is a pathognomonic marker of TYR I, and its detection by NBS MS/MS is possible. This review of the current status of NBS for TYR I in the US is the result of discussions at the HHS Secretary's (Discretionary) Advisory Committee on Heritable Disorders in Newborns and Children about the inconsistent implementation of effective NBS for TYR I in the US. We sought to understand the different TYR I screening practices in US NBS programs. Results indicate that 50 out of 51 NBS programs in the US screen for TYR I, and a successful SUAC performance evaluation scheme is available from the Centers for Disease Control and Prevention. Programmatic and methodological barriers were identified that prevent widespread adoption of SUAC measurements in NBS laboratories. However, since SUAC detection is currently the best approach to NBS for TYR I, a further delay of the addition of SUAC measurement into NBS procedures is discouraged. SUAC measurement should improve both the false positive and false negative rate in NBS for TYR I thereby yielding the desired benefits for affected patients at no expense to the overall population served.

The purpose of this study was to determine whether there are underlying dimensions common among traditional traumatic brain injury (TBI) severity indices and, if so, the extent to which they are interchangeable when predicting short-term outcomes. This study had an observational design, and took place in United States trauma centers reporting to the National Trauma Data Bank (NTDB). The sample consisted of 77,470 unweighted adult cases reported to the NTDB from 2007 to 2010, with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) TBI codes. There were no interventions. Severity indices used were the Emergency Department Glasgow Coma Scale (GCS) Total score and each of the subscales for eye opening (four levels), verbal response (five levels), and motor response (six levels); the worst Abbreviated Injury Scale (AIS) severity score for the head (six levels); and the worst Barell index type (three categories). Prediction models were computed for acute care length of stay (days), intensive care unit length of stay (days), hospital discharge status (alive or dead), and, if alive, discharge disposition (home versus institutional). Multiple correspondence analysis (MCA) indicated a two dimensional relationship among items of severity indexes. The primary dimension reflected overall injury severity. The second dimension seemed to capture volitional behavior without the capability for cogent responding. Together, they defined two vectors around which most of the items clustered. A scale that took advantage of the order of items along these vectors proved to be the most consistent index for predicting short-term health outcomes. MCA provided useful insight into the relationships among components of traditional TBI severity indices. The two vector pattern may reflect the impact of injury on different cortical and subcortical networks. Results are discussed in terms of score substitution and the ability to impute missing values.

OBJECTIVE: To estimate the number of adults in the United States from 2006 to 2012 who manifest selected health and social outcomes 5 years following a traumatic brain injury (TBI) that required acute inpatient rehabilitation. DESIGN: Secondary data analysis. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients 16 years and older receiving acute inpatient rehabilitation for a primary diagnosis of TBI. MAIN OUTCOME MEASURES: Mortality, functional independence, societal participation, subjective well-being, and global outcome. RESULTS: Annually from 2001 to 2007, an average of 13 700 patients aged 16 years or older received acute inpatient rehabilitation in the United States with a primary diagnosis of TBI. Approximately 1 in 5 patients had died by the 5-year postinjury assessment. Among survivors, 12% were institutionalized and 50% had been rehospitalized at least once. Approximately one-third of patients were not independent in everyday activities. Twenty-nine percent were dissatisfied with life, with 8% reporting markedly depressed mood. Fifty-seven percent were moderately or severely disabled overall, with 39% having deteriorated from a global outcome attained 1 or 2 years postinjury. Of those employed preinjury, 55% were unemployed. Poorer medical, functional, and participation outcomes were associated with, but not limited to, older age. Younger age groups had poorer mental and emotional outcomes. Deterioration in global outcome was common and not age-related. CONCLUSIONS: Significant mortality and morbidity were evident at 5 years postinjury. The deterioration in global outcomes observed regardless of age suggests that multiple influences contribute to poorer outcomes. Public health interventions intended to reduce post-acute inpatient rehabilitation mortality and morbidity rates will need to be multifaceted and age-specific.

OBJECTIVE: To estimate the overall and by age-group characteristics at admission and discharge from rehabilitation between 2001 and 2010 of all late-teens and adults undergoing inpatient rehabilitation for a primary diagnosis of traumatic brain injury (TBI) in the United States. DESIGN: Secondary data analysis. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients aged 16 years and older receiving inpatient rehabilitation for a primary diagnosis of TBI between 2001 and 2010. MAIN OUTCOME MEASURES: Functional independence, level of disability, and living situation. RESULTS: The incidence of TBI by age group found the largest proportion of cases to be aged 80 years and older, with a gradual decline in incidence in the age group of 30 years, at which point there was a slight increase. Injuries resulted predominantly from falls (49.8%) and motor vehicle crashes (40.8%); however, injuries to the youngest individuals were largely from motor vehicle crashes with decreasing rates as age increased, while injuries due to falls rose as age increased, with the oldest age groups most likely to incur a TBI. Preinjury alcohol misuse and substance use were found to occur in 22.9% and 12.2% of the total population, respectively; however, age distributions demonstrated high preinjury use among individuals younger than 50 years (eg, 46.4% and 30.6% for those aged 20 and 29 years, respectively) with decreasing misuse as age increased. Of the total population, 49.2% were retired, 31.1% employed, 14.1% not working, and 5.6% students. Trends by age showed that younger individuals were more likely to be students or employed (eg, 14.5% and 62.0% for those aged 20 and 29 years, respectively), with employment status peaking for those aged 30 to 39 years, and declining to 3.2% for the oldest age group (80 years and older). The trend of person(s) living alone between pre- and postrehabilitation showed the least amount of change for those aged 16 to 19 years with steadily increasing changes as age increased. Similar trends were seen for residence changes pre- and postrehabilitation, with the youngest most likely to return to living at a private residence, and a gradual decrease in return to living at a private residence as age increased. FIM instrument ("FIM") Motor and Cognitive subscale scores demonstrated that younger individuals had lower scores at admission to rehabilitation and higher scores at rehabilitation discharge. CONCLUSION: This study provides population estimates for all patients 16 years of age and older receiving inpatient rehabilitation for a primary diagnosis of TBI in the United States between 2001 and 2010. A recent trend shows the aging of the inpatient TBI rehabilitation population. Many characteristics important to rehabilitation outcomes are influenced by age, with older individuals trending toward being female, having less severe TBIs, incurring TBIs as a result of falls, but showing less improvement during rehabilitation, greater resulting disability, and more changes in their living situation postrehabilitation. These findings are of particular interest, as the oldest age groups considered in these analyses did not include the baby boom population.

Individuals 65 years of age and over have the highest rates of traumatic brain injury (TBI)-related hospitalizations and deaths, and older adults (defined variably across studies) have particularly poor outcomes after TBI. The factors predicting these outcomes remain poorly understood, and age-specific care guidelines for TBI do not exist. This study provides an overview of TBI in older adults using data from the National Trauma Data Bank (NTDB) gathered between 2007 and 2010, evaluates age group-specific trends in rates of TBI over time using U.S. Census data, and examines whether routinely collected information is able to predict hospital discharge status among older adults with TBI in the NTDB. Results showed a 20-25% increase in trauma center admissions for TBI among the oldest age groups (those >=75 years), relative to the general population, between 2007 and 2010. Older adults (>=65 years) with TBI tended to be white females who have incurred an injury from a fall resulting in a "severe" Abbreviated Injury Scale (AIS) score of the head. Older adults had more in-hospital procedures, such as neuroimaging and neurosurgery, tended to experience longer hospital stays, and were more likely to require continued medical care than younger adults. Older age, injury severity, and hypotension increased the odds of in-hospital death. The public health burden of TBI among older adults will likely increase as the Baby Boom generation ages. Improved primary and secondary prevention of TBI in this cohort is needed.

Biochemical genetic testing and newborn screening are essential laboratory services for the screening, detection, diagnosis, and monitoring of inborn errors of metabolism or inherited metabolic disorders. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized on the basis of the level of testing complexity as either waived (i.e., from routine regulatory oversight) or nonwaived testing (which includes tests of moderate and high complexity). Laboratories that perform biochemical genetic testing are required by CLIA regulations to meet the general quality systems requirements for nonwaived testing and the personnel requirements for high-complexity testing. Laboratories that perform public health newborn screening are subject to the same CLIA regulations and applicable state requirements. As the number of inherited metabolic diseases that are included in state-based newborn screening programs continues to increase, ensuring the quality of performance and delivery of testing services remains a continuous challenge not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories. To help ensure the quality of laboratory testing, CDC collaborated with the Centers for Medicare & Medicaid Services, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health to develop guidelines for laboratories to meet CLIA requirements and apply additional quality assurance measures for these areas of genetic testing. This report provides recommendations for good laboratory practices that were developed based on recommendations from the Clinical Laboratory Improvement Advisory Committee, with additional input from the Secretary's Advisory Committee on Genetics, Health, and Society; the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; and representatives of newborn screening laboratories. The recommended practices address the benefits of using a quality management system approach, factors to consider before introducing new tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations are intended for laboratories that perform biochemical genetic testing to improve the quality of laboratory services and for newborn screening laboratories to ensure the quality of laboratory practices for inherited metabolic disorders. These recommendations also are intended as a resource for medical and public health professionals who evaluate laboratory practices, for users of laboratory services to facilitate their collaboration with newborn screening systems and use of biochemical genetic tests, and for standard-setting organizations and professional societies in developing future laboratory quality standards and practice recommendations. This report complements Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions (CDC. Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR 2009;58 [No. RR-6]) to provide guidance for ensuring and improving the quality of genetic laboratory services and public health outcomes. Future recommendations for additional areas of genetic testing will be considered on the basis of continued monitoring and evaluation of laboratory practices, technology advancements, and the development of laboratory standards and guidelines.

OBJECTIVE: To extend the representativeness of the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) for individuals 16 years and older, admitted for acute, inpatient rehabilitation in the United States with a primary diagnosis of traumatic brain injury (TBI) analyses completed by Corrigan and colleagues by comparing this data set to national data for patients admitted to inpatient rehabilitation with identical inclusion criteria that included 3 additional years of data and 2 new demographic variables. DESIGN: Secondary analysis of existing data sets and extension of previously published analyses. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients 16 years and older with a primary rehabilitation diagnosis of TBI; the US TBI Rehabilitation population, n=156,447; and the TBIMS-NDB population, n=7373. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Demographics, functional status, and length of stay in hospital. RESULTS: The TBIMS-NDB was largely representative of patients 16 years and older, admitted for rehabilitation in the United States with a primary diagnosis of TBI on or after October 1, 2001, and discharged as of December 31, 2010. The results of the extended analyses were similar to those reported by Corrigan and colleagues. Age accounted for the largest difference between the samples, with the TBIMS-NDB including a smaller proportion of patients 65 years and older than all those admitted for rehabilitation with a primary diagnosis of TBI in the United States. After partitioning each data set at age 65, most distributional differences found between samples were markedly reduced; however, differences in the preinjury vocational status of the employed and rehabilitation lengths of stay between 1 and 9 days remained robust. The subsamples of patients 64 years and younger were found to differ only slightly on all remaining variables, whereas those 65 years and older were found to have meaningful differences in insurance type and age distribution. CONCLUSIONS: These results reconfirm that the TBIMS-NDB is largely representative of patients with TBI receiving inpatient rehabilitation in the United States. Differences between the 2 data sets were found to be stable across the 3 additional years of data, and new differences were limited to those involving newly introduced variables. To use these data for population-based research, it is strongly recommended that statistical adjustment be conducted to account for the lower percentage of patients older than 65 years, inpatient rehabilitation stays less than 10 days, and preinjury vocational status in the TBIMS-NDB.

OBJECTIVE: To determine whether the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) is representative of individuals aged 16 years and older admitted for acute, inpatient rehabilitation in the United States with a primary diagnosis of traumatic brain injury (TBI). DESIGN: Secondary analysis of existing data sets. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients aged 16 years and older with a primary rehabilitation diagnosis of TBI. MAIN OUTCOME MEASURES: Demographic characteristics, functional status, and hospital length of stay. RESULTS: Patients included in the TBIMS-NDB from October 2001 through December 2007 were largely representative of all individuals 16 years and older admitted for rehabilitation in the United States with a primary diagnosis of TBI. The major difference in distribution was age-the TBIMS-NDB cohort did not include as large a proportion of patients older than 65 years as were admitted for rehabilitation with a primary diagnosis of TBI in the United States. Distributional differences for age-related characteristics were observed; however, groups of patients partitioned at aged 65 years differed minimally, especially within the younger than 65 years subset. Regardless of age, the proportion of patients with a rehabilitation stay of 1 to 9 days was larger nationwide. Nationwide admissions showed an age distribution similar to patients discharged alive from acute care with moderate, severe or penetrating TBI. The proportion of patients aged 70 years and older admitted for TBI rehabilitation in the United States increased every year, a trend that was not evident in the general population, TBIMS-NDB or among TBI patients in acute care. CONCLUSIONS: These results provide substantial empirical evidence that the TBIMS-NDB is representative of patients receiving inpatient rehabilitation for TBI in the United States. Researchers utilizing the TBIMS-NDB may want to adjust statistically for the lower percentage of patients older than 65 years or those with stays less than 10 days.

OBJECTIVE: To identify factors predicting acute hospital discharge disposition after moderate to severe traumatic brain injury (TBI). DESIGN: Secondary analysis of existing datasets. SETTING: Acute care hospitals. PARTICIPANTS: Adults hospitalized with moderate to severe TBI included in 3 large sets of archival data: (1) Centers for Disease Control and Prevention Central Nervous System Injury Surveillance database (n=15,646); (2) the National Trauma Data Bank (n=52,012); and (3) the National Study on the Costs and Outcomes of Trauma (n=1286). INTERVENTIONS: None. MAIN OUTCOME MEASURE: Discharge disposition from acute hospitalization to 1 of 3 postacute settings: (1) home, (2) inpatient rehabilitation, or (3) subacute settings, including nursing homes and similar facilities. RESULTS: The Glasgow Coma Scale (GCS) score and length of acute hospital length of stay (LOS) accounted for 35% to 44% of the variance in discharges to home versus not home, while age and sex added from 5% to 8%, and race/ethnicity and hospitalization payment source added another 2% to 5%. When predicting discharge to rehabilitation versus subacute care for those not going home, GCS and LOS accounted for 2% to 4% of the variance, while age and sex added 7% to 31%, and race/ethnicity and payment source added 4% to 5%. Across the datasets, longer LOS, older age, and white race increased the likelihood of not being discharged home; the most consistent predictor of discharge to rehabilitation was younger age. CONCLUSIONS: The decision to discharge to home a person with moderate to severe TBI appears to be based primarily on severity-related factors. In contrast, the decision to discharge to rehabilitation rather than to subacute care appears to reflect sociobiologic and socioeconomic factors; however, generalizability of these results is limited by the restricted range of potentially important variables available for analysis.

BACKGROUND: Newborn screening (NBS) for inborn errors of propionate, methionine, and cobalamin metabolism relies on finding abnormal concentrations of methionine and propionylcarnitine. These analytes are not specific for these conditions and lead to frequent false-positive results. More specific markers are total homocysteine (tHCY), methylmalonic acid (MMA), and methylcitric acid (MCA), but these markers are not detected by current NBS methods. To improve this situation, we developed a method for the detection of tHCY, MMA, and MCA in dried blood spots (DBSs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: The analytes were extracted from a single 4.8-mm DBS punch with acetonitrile:water:formic acid (59:41:0.42) containing dithiothreitol and isotopically labeled standards (d(3)-MMA, d(3)-MCA, d(8)-homocystine). The extract was dried and treated with 3 N HCl in n-butanol to form butylesters. After evaporation of the butanol, the residue was reconstituted and centrifuged and the supernatant was subjected to LC-MS/MS analysis. Algorithms were developed to apply this method as an efficient and effective second-tier assay on samples with abnormal results by primary screening. RESULTS: The 99th percentiles determined from the analysis of 200 control DBSs for MMA, MCA, and HCY were 1.5, 0.5, and 9.8 mumol/L, respectively. Since 2005, prospective application of this second-tier analysis to 2.3% of all NBS samples led to the identification of 13 affected infants. CONCLUSIONS: Application of this assay reduced the false-positive rate and improved the positive predictive value of NBS for conditions associated with abnormal propionylcarnitine and methionine concentrations.