Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S.

OBJECTIVE: Compare survival in patients with multiple sclerosis (MS) from a U.S. commercial health insurance database with a matched cohort of non-MS subjects. METHODS: 30,402 MS patients and 89,818 non-MS subjects (comparators) in the OptumInsight Research (OIR) database from 1996 to 2009 were included. An MS diagnosis required at least 3 consecutive months of database reporting, with two or more ICD-9 codes of 340 at least 30 days apart, or the combination of 1 ICD-9-340 code and at least 1 MS disease-modifying treatment (DMT) code. Comparators required the absence of ICD-9-340 and DMT codes throughout database reporting. Up to three comparators were matched to each patient for: age in the year of the first relevant code (index year - at least 3 months of reporting in that year were required); sex; region of residence in the index year. Deaths were ascertained from the National Death Index and the Social Security Administration Death Master File. Subjects not identified as deceased were assumed to be alive through the end of 2009. RESULTS: Annual mortality rates were 899/100,000 among MS patients and 446/100,000 among comparators. Standardized mortality ratios compared to the U.S. population were 1.70 and 0.80, respectively. Kaplan-Meier analysis yielded a median survival from birth that was 6 years lower among MS patients than among comparators. CONCLUSIONS: The results show, for the first time in a U.S. population, a survival disadvantage for contemporary MS patients compared to non-MS subjects from the same healthcare system. The 6-year decrement in lifespan parallels a recent report from British Columbia.

An electronic simulator for testing infant apnoea monitors that uses actual physiologic data.

An electronic simulator of physiologic signals used in infant monitoring has been designed, constructed and applied in the Collaborative Home Infant Monitor Evaluation (CHIME). A unique feature of the simulator is that it contains actual physiologic waveforms recorded from infants rather than artificial, idealized signals. The simulator stores breathing waveforms that can be used to test transthoracic-impedance- and inductance-plethysmography-based monitors, and heart rate channels are tested by playing a neonatal QRS complex at preset fixed rates or a variable rate as determined from infant recordings. The transfer characteristics of the simulator are constant over frequencies ranging from 0.5 to 8 Hz for the respiration channels. Data stored in memory are divided into 60 second epochs that can be presented to the monitor being tested in a programmable sequence. A group of 66 CHIME monitors was tested using a simulator programmed with 17 apnoea and bradycardia waveforms. The agreement between monitors as to the duration of detected apnoea decreases as the amount of artefact in the signal increases. Discrepancies between monitors in detecting apnoea duration were found to be similar to inconsistencies between CHIME investigators manually scoring similar waveforms.

Cardiopulmonary monitoring at home: the CHIME monitor.

A new physiologic monitor for use in the home has been developed and used for the Collaborative Home Infant Monitor Evaluation (CHIME). This monitor measures infant breathing by respiratory inductance plethysmography and transthoracic impedance; infant electrocardiogram, heart rate and R-R interval; haemoglobin O2 saturation of arterial blood at the periphery and sleep position. Monitor signals from a representative sample of 24 subjects from the CHIME database were of sufficient quality to be clinically interpreted 91.7% of the time for the respiratory inductance plethysmograph, 100% for the ECG, 99.7% for the heart rate and 87% for the 16 subjects of the 24 who used the pulse oximeter. The monitor detected breaths with a sensitivity of 96% and a specificity of 65% compared to human scorers. It detected all clinically significant bradycardias but identified an additional 737 events where a human scorer did not detect bradycardia. The monitor was considered to be superior to conventional monitors and, therefore, suitable for the successful conduct of the CHIME study.

Cardiorespiratory events recorded on home monitors: Comparison of healthy infants with those at increased risk for SIDS.

CONTEXT: Home monitors designed to identify cardiorespiratory events are frequently used in infants at increased risk for sudden infant death syndrome (SIDS), but the efficacy of such devices for this use is unproven. OBJECTIVE: To test the hypothesis that preterm infants, siblings of infants who died of SIDS, and infants who have experienced an idiopathic, apparent life-threatening event have a greater risk of cardiorespiratory events than healthy term infants. DESIGN: Longitudinal cohort study conducted from May 1994 through February 1998. SETTING: Five metropolitan medical centers in the United States. PARTICIPANTS: A total of 1079 infants (classified as healthy term infants and 6 groups of those at risk for SIDS) who, during the first 6 months after birth, were observed with home cardiorespiratory monitors using respiratory inductance plethysmography to detect apnea and obstructed breathing. MAIN OUTCOME MEASURES: Occurrence of cardiorespiratory events that exceeded predefined conventional and extreme thresholds as recorded by the monitors. RESULTS: During 718 358 hours of home monitoring, 6993 events exceeding conventional alarm thresholds occurred in 445 infants (41%). Of these, 653 were extreme events in 116 infants (10%), and of those events with apnea, 70% included at least 3 obstructed breaths. The frequency of at least 1 extreme event was similar in term infants in all groups, but preterm infants were at increased risk of extreme events until 43 weeks' postconceptional age. CONCLUSIONS: In this study, conventional events are quite common, even in healthy term infants. Extreme events were common only in preterm infants, and their timing suggests that they are not likely to be immediate precursors to SIDS. The high frequency of obstructed breathing in study participants would likely preclude detection of many events by conventional techniques. These data should be important for designing future monitors and determining if an infant is likely to be at risk for a cardiorespiratory event.

The effect of epoch length and smoothing on infant sleep and waking state architecture for term infants at 42 to 46 weeks postconceptional age.

STUDY OBJECTIVES: Epoch lengths from 20 seconds to 1 minute, and smoothing strategies from zero to three minutes are encountered in the infant sleep and waking literature. The present study systematically examined the impact of various epoch lengths and smoothing strategies on infant sleep state architecture. DESIGN: Overnight polysomnographic recordings were visually assessed by epoch as wake or as each of four sleep state parameters: electroencephalographic patterns, respiration, body movement, and eye movement. From these findings, sleep and waking states were assigned for each of six combinations of epoch length (30-second or 1-minute) and smoothing window length (none, 3-epoch, or 5-epoch). SETTING: N/A. PARTICIPANTS: Subjects were 91 term infants, 42-46 weeks postconceptional age, from the Collaborative Home Infant Monitoring Evaluation (CHIME) study. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A greater epoch length resulted in more active and less quiet sleep as a percentage of total study; however, the size of the smoothing window did not affect the percentage of sleep/waking states. In general, the greater the epoch length and the greater the smoothing window length, the fewer the number of, the greater the mean duration of, and the greater the longest continuous episode of sleep/waking states. Analysis of significant interactions indicated that a 1-minute epoch length relative to a 30-second epoch length resulted in increasingly longer episodes of quiet and especially active sleep with a greater smoothing window length. CONCLUSIONS: Smoothing strategy significantly altered sleep state architecture in infants and may explain part of the variability in infant sleep state findings between laboratories.

Comparison of apnea identified by respiratory inductance plethysmography with that detected by end-tidal CO(2) or thermistor. The CHIME Study Group.

As part of the Collaborative Home Infant Monitoring Evaluation (CHIME) we compared apnea identified by a customized home monitor using respiratory inductance plethysmography (RIP) with simultaneously recorded polysomnography-acquired nasal end-tidal CO(2) (PET(CO(2))) and nasal/oral thermistor in 422 infants during overnight laboratory recordings to determine concordance between techniques, sources of disagreement, and capacity of RIP to detect obstructed breaths within an apnea. Among 233 episodes of apnea identified by at least one method as >/= 16 s, 120 were observed by the CHIME monitor, 219 by PET(CO(2)), and 163 by thermistor. The positive predictive value of the CHIME-identified apnea was 89.2% (95% CI 83, 95) and 73% (95% CI 65, 81) for PET(CO(2)) and thermistor, respectively. However, the sensitivity of the CHIME monitor in identifying events detected by the other methods was only approximately 50%. Among 87 apnea events identified by all three techniques, no two methods showed high agreement in measurement of apnea duration: RIP and PET(CO(2)) (ICC = 0.54), RIP and thermistor (ICC = 0.13), PET(CO(2)) and nasal thermistor (ICC = 0.41). Among the 179 breaths identified by RIP as obstructed, 79.9% were judged to be obstructed on the PET(CO(2)) and 80.4% were judged to be obstructed on the thermistor channel. Among 238 breaths identified on PET(CO(2)) as obstructed, 54.2% were determined to be obstructed by RIP. Among 204 breaths identified on thermistor as obstructed, 55. 4% were determined to be obstructed by RIP. Reasons for discrepancies in apnea detection among channels included body movement, partial airway obstruction, and obstructed breaths. Despite these limitations the CHIME monitor provides an opportunity to record physiological data previously unavailable in the home.

Agreement among raters in assessment of physiologic waveforms recorded by a cardiorespiratory monitor for home use. Collaborative Home Infant Monitoring Evaluation (CHIME) Study Group.

There are numerous reports of cardiorespiratory patterns in infants on home monitors, but no data to determine whether "experts" agree on the description of these patterns. Therefore, we evaluated agreement among four experienced investigators and five trained technicians who assessed independently the same sample of physiologic waveforms recorded from infants enrolled in a multicenter study. The monitor used respiratory inductance plethysmography and recorded waveforms for apnea > or = 16 s or a heart rate < 80 beats/min for > or = 5 s. The investigators and technicians initially assessed 88 waveforms. After additional training, the technicians assessed another 113 additional waveforms. In categorizing waveforms as apnea present or absent, agreement among technicians improved considerably with additional training (kappa 0.65 to 0.85). For categorizing waveforms as having bradycardia present versus absent, the trends were the same. Agreement in measurement of apnea duration also improved considerably with additional training (intraclass correlation 0.33-0.83). Agreement in measurement of bradycardia duration was consistently excellent (intraclass correlation 0.86-0.99). Total agreement was achieved among technicians with additional training for measurement of the lowest heart rate during a bradycardia. When classifying apnea as including > or = 1, > or = 2, > or = 3, or > or = 4 out-of-phase breaths, agreement was initially low, but after additional training it improved, especially in categorization of apneas with > or = 3 or > or = 4 out-of-phase breaths (kappa 0.67 and 0.94, respectively). Although researchers and clinicians commonly describe events based on cardiorespiratory recordings, agreement amongst experienced individuals may be poor, which can confound interpretation. With clear guidelines and sufficient training raters can attain a high level of agreement in describing cardiorespiratory events.

Infant polysomnography: reliability. Collaborative Home Infant Monitoring Evaluation (CHIME) Steering Committee.

Infant polysomnography (IPSG) is an increasingly important procedure for studying infants with sleep and breathing disorders. Since analyses of these IPSG data are subjective, an equally important issue is the reliability or strength of agreement among scorers (especially among experienced clinicians) of sleep parameters (SP) and sleep states (SS). One basic issue of this problem was examined by proposing and testing the hypothesis that infant SP and SS ratings can be reliably scored at substantial levels of agreement, that is, kappa (kappa) > or = 0.61. In light of the importance of IPSG reliability in the collaborative home infant monitoring evaluation (CHIME) study, a reliability training and evaluation process was developed and implemented. The bases for training on SP and SS scoring were CHIME criteria that were modifications and supplements to Anders, Emde, and Parmelee (10). The kappa statistic was adopted as the method for evaluating reliability between and among scorers. Scorers were three experienced investigators and four trainees. Inter- and intrarater reliabilities for SP codes and SSs were calculated for 408 randomly selected 30-second epochs of nocturnal IPSG recorded at five CHIME clinical sites from healthy full term (n = 5), preterm (n = 4), apnea of infancy (n = 2), and siblings of the sudden infant death syndrome (SIDS) (n = 4) enrolled subjects. Infant PSG data set 1 was scored by both experienced investigators and trained scorers and was used to assess initial interrater reliability. Infant PSG data set 2 was scored twice by the trained scorers and was used to reassess inter-rater reliability and to assess intrarater reliability. The kappa s for SS ranged from 0.45 to 0.58 for data set 1 and represented a moderate level of agreement. Therefore, rater disagreements were reviewed, and the scoring criteria were modified to clarify ambiguities. The kappa s and confidence intervals (CIs) computed for data set 2 yielded substantial inter-rater and intrarater agreements for the four trained scorers; for SS, the kappa = 0.68 and for SP the kappa s ranged from 0.62 to 0.76. Acceptance of the hypothesis supports the conclusion that the IPSG is a reliable source of clinical and research data when supported by significant kappa s and CIs. Reliability can be maximized with strictly detailed scoring guidelines and training.

Newborn acoustic cry characteristics of infants subsequently dying of sudden infant death syndrome.

OBJECTIVE: To test the hypothesis that the occurrence of a neonatal cry exhibiting a high first formant is a risk factor for sudden infant death syndrome (SIDS) and to evaluate the association between SIDS and other acoustic cry variables. METHOD: We recorded cries and obtained medical and demographic data for 21,880 apparently healthy term newborns. Two cries were recorded between days 2 and 7 of life, after a painful stimulus at the time of routine blood drawing. Acoustic variables were measured with an automated computer-based analysis system. Twelve infants died of SIDS. Age at death ranged from 19 days to 6.5 months. Autopsies were performed in all cases. At least one cry was analyzed for all 12 infants who died of SIDS and 20,167 infants without SIDS. Two cries were analyzed for 9 infants who died of SIDS and 14,235 infants without SIDS. RESULTS: Newborns whose first cries exhibited a high first formant were more likely to die of SIDS than infants whose first cries did not have this characteristic (relative risk, 3.5; 95% confidence interval [CI], 1.1 to 12). The relative risk for SIDS increased to 8.8 (95% CI, 2.2 to 35) for newborns whose second cries showed that this characteristic persisted. Newborns with the combination of both a high first formant and a high number of mode changes on both of two cries had a relative risk of 32 (95% CI, 8.7 to 120). CONCLUSIONS: We have shown an association between alterations in neonatal cry acoustics and SIDS. Cry analysis represents a potentially important research tool that, when studied in relation to other physiologic measures, may lead to an improved understanding of SIDS.

Developmental outcome as a function of the goodness of fit between the infant's cry characteristics and the mother's perception of her infant's cry.

OBJECTIVE: To determine whether the "goodness of fit" between infant cry characteristics and the mother's perception of the cry is related to developmental outcome at 18 months of age. DESIGN: This was a prospective, longitudinal study from birth to 18 months performed in a blinded manner. SETTING: The study was conducted in a maternity hospital, including normal and special care nurseries and a laboratory for developmental follow-up. PATIENTS: The 121 term and preterm infants and their mothers were selected to meet medical criteria. MEASUREMENT: Acoustic analysis of 1-month infant cry and the mother's perception of the same cry was used to divide subjects into four groups representing matches and mismatches between infant cry characteristics and maternal cry perception. Primary outcome measures of cognitive, language, motor, and neurologic outcome were administered at 18 months. Caretaking environment measures were also recorded. RESULTS: Statistically significant (P < .05) findings showed that matched groups scored higher on measures of language and cognitive performance than infants in the mismatch groups, with a particular advantage for infants in the matched group in which mothers accurately perceived the higher-pitched cries of their infants. There were no differences between the groups in biologic or sociodemographic factors. Group differences were observed in social support and maternal self-esteem. CONCLUSIONS: Matches and mismatches between infant cry characteristics at 1 month and the mother's perception of the cry are related to cognitive and language outcome at 18 months in term and preterm infants. This relation is probably due to transactional processes in which developmental outcome is affected by the clarity of the infants' signals and by the ability of the mother to accurately perceive her infant's signals. The mother's ability to read her infant's cues may be affected by factors such as social support and self-esteem.

Neurobehavioral syndromes in cocaine-exposed newborn infants.

The effects of fetal cocaine exposure on newborn cry characteristics were studied in 80 cocaine-exposed and 80 control infants. The groups were stratified to be similar on maternal demographic characteristics and maternal use of other illegal substances and alcohol during pregnancy. The hypothesis was that excitable cry characteristics were related to the direct effects of cocaine, while depressed cry characteristics were related to the indirect effects of cocaine secondary to low birthweight. Structural equation modeling (EQS) showed direct effects of cocaine on cries with a longer duration, higher fundamental frequency, and a higher and more variable first formant frequency. Indirect effects of cocaine secondary to low birthweight resulted in cries with a longer latency, fewer utterances, lower amplitude, and more dysphonation. Cocaine-exposed infants had a lower birthweight, shorter length, and smaller head circumference than the unexposed controls. Findings were consistent with the notion that 2 neurobehavioral syndromes, excitable and depressed, can be described in cocaine-exposed infants, and that these 2 syndromes are due, respectively, to direct neurotoxic effects and indirect effects secondary to intrauterine growth retardation.

Abnormal brain-stem function (brain-stem auditory evoked response) correlates with acoustic cry features in term infants with hyperbilirubinemia.

We hypothesized that changes in brain-stem auditory evoked responses related to bilirubin would be associated with changes in cry because of the anatomic proximity in the brain stem of cranial nerves 8 (auditory) and 9 to 12 (vagal complex, which controls cry). Brain-stem auditory evoked responses and computerized cry analysis were used to study the concurrent effects of moderate hyperbilirubinemia on auditory function and cry. Fifty term infants were divided equally into two groups on the basis of serum bilirubin concentrations: low (less than 8 mg/dl; 136) mumol/L and moderate (10 to 20 mg/dl, 170 to 342 mumol/L). Forty-three infants had successful tracings of brain-stem auditory evoked responses recorded with a Cadwell model 5200A evoked response unit during two successive trials, and a cry recording of each infant was analyzed by computer. The moderate serum bilirubin group had an increase in percent cry phonation (p less than 0.02) and an increase in the variability of the first formant (p less than 0.04) in comparison with the low serum bilirubin group. Serum bilirubin values correlated positively with brain-stem conduction time (r = 0.36, p less than 0.01), percent phonation (r = 0.42, p less than 0.004), and variability of the first formant (r = 0.39, p less than 0.02). Percent phonation, the voiced component produced by increased neural control, correlated with the interpeak of waves latencies I to III (r = 0.32, p less than 0.03) and brain-stem conduction time (wave I to V) (r = 0.35, p less than 0.01). We conclude that hyperbilirubinemia affects adjoining areas of the brain stem that control hearing and cry production.

Assessment of infant cry variability in high-risk infants.

Two studies were conducted to determine the relationship between variability in acoustic features of the infant cry and medical risk factors. In study 1, 3 groups of preterm infants (healthy, sick and CNS pathology) were compared with term infants at 40 weeks gestational age. The cry was analyzed by computer. The coefficient of variability of cry amplitude and the formant features of the cry differed among the groups of preterm infants. In study 2, 3 groups of term infants at low, moderate and high levels of hyperbilirubinemia were compared on the cry measures. More variability in the formant features of the cry was found in infants with higher levels of bilirubin. The correlation between the coefficient of variation in the cry formants and level of bilirubin was statistically significant. These two studies suggest that variability in the acoustic features of the cry relate to the medical status of the infant and may provide a measure of neurophysiological integrity.