High Rate of Emergency Department Care in Youth With Abdominal Pain-Associated Functional Gastrointestinal Disorders.

OBJECTIVES: The primary objective was to describe patterns of care delivery locations in youth with abdominal pain-associated functional gastrointestinal disorders (AP-FGID) and assess for differences in patterns of care delivery by sex and race. A secondary objective was to describe cost variability within the emergency department (ED). METHODS: Data were obtained using a large, single-vendor database that extracts and deidentifies data from the electronic health record across the outpatient, ED, and inpatient continuum of care. We evaluated patients 8 to 17 years of age seen over an 8-year period for a priority 1 diagnosis of an AP-FGID. Data collected included age, sex, race, encounter location, and total cost of ED encounters. We specifically assessed how often patients seen in the ED were also seen in outpatient or inpatient settings. RESULTS: A total of 53,750 patients (64% female; mean age, 13.3 ± 2.8 years) were identified and assessed. The most common location of care was the ED (48.8%) followed by the outpatient setting (46.2%). Of patients seen for a priority 1 AP-FGID diagnosis in the ED, only 3.7% were seen for a priority 1 diagnosis in the outpatient setting, and only 1% were seen in an inpatient setting. Overall, females received 42.5% of their care and males received 44.8% of their care in the ED. The overall rate of ED care was 66.9% for Hispanic, 61.5% for African American, 55.1% for Asian, 46.6% for Native American, and 36.9% for Caucasian patients. CONCLUSIONS: The ED is the most common location for care for youth with AP-FGIDs and, for the majority, seems to be the only location. This seems to be particularly true for Hispanic and African American patients. Given the often complex psychosocial needs of this patient group, processes need to be developed to transition these patients into the outpatient setting, ideally to programs specializing in chronic pain.

Rates and Predictors of Using Opioids in the Emergency Department to Treat Migraine in Adolescents and Young Adults.

OBJECTIVES: This study aimed to determine the rate and context in which opioids are used to treat migraine in adolescents and young adults seen in emergency care settings. METHODS: Data from 2010 to 2016 in the Cerner Health Facts electronic health record data warehouse were analyzed using multilevel logistic regression to estimate the population likelihood of an opioid being used in the emergency department (ED) to treat a primary diagnosis of migraine in adolescents and young adults and to evaluate the extent to which this likelihood varies as a function of characteristics of the patient (age, sex, race, and insurance), encounter (referral source, provider specialty, and encounter duration and year), and ED (region, setting, size, payer mix, and academic status). RESULTS: The study identified 14,494 eligible ED encounters with unique patients, of which 23% involved an opioid. Likelihood of being treated with opioids was significantly higher for patients who were older, female, white, and seen by a surgeon and who had longer encounters and encounters earlier in the time period sampled. Sites varied widely in percentage of encounters involving opioids (mean, 26.4% ± 20.1%; range, 0-100%), with higher rates associated with smaller sites with relatively higher proportions of commercially insured patients. CONCLUSIONS: Use of opioids in the ED to treat migraine in youth is fairly common, with rate variation reflecting broader trends in for whom opioids tend to be more likely to be prescribed. These findings may be helpful for benchmarking and informing quality improvement efforts aimed at reducing unwarranted opioid exposure in youth.

Gastric cancer in the pediatric population, a multicenter cross-sectional analysis of presentation and coexisting comorbidities.

OBJECTIVES: Solid tumors of the stomach in children are rare, adenocarcinoma being most frequently reported. Risk factors and clinical presentation are poorly understood. We undertook a nationwide database analysis to evaluate pediatric CA stomach presentation, comorbidities, and metastatic pattern. METHODS: The Cerner Health Facts Database® (CHFD) was queried for pediatric age range (1-21) patients, 2010-2017 inclusive. The pediatric gastric cancer cohort was defined by ICD9 and ICD 10 CM diagnoses attributable to primary (non-GIST, non-hematologic) solid tumors of the stomach limited to diagnosis priority < 5 and validated by filtering for supportive diagnoses. Demographic characteristics, comorbidities, before and throughout the medical record were analyzed and compared to the base population. RESULTS: The cohort included 333 patients from a base population of 9.6 million children. The M:F ratio was 1.15:1, mean age at diagnosis was 11.8 years. Stomach cancer was most prevalent in non-Hispanic whites, less in Asians and African Americans. Symptoms included abdominal pain, vomiting, anemia, diarrhea and weight loss. Reflux symptoms, esophagitis, gastritis, including H. pylori and duodenitis were reported in 10.2%. Obesity, obesity-related comorbidities, tobacco exposure and family history of colonic polyps, gastrointestinal and breast cancer were all more prevalent (P < 0.0001) in the cohort. DISCUSSION: We defined patient demographic characteristics, anatomic distribution in a large cohort of children with solid tumors of the stomach. Reported symptoms in our cohort are similar to those observed in adults. Associated comorbidities which may reflect risk factors include obesity, tobacco exposure and family history of intestinal polyps and malignancy.

Estimating the prevalence of neurosurgical interventions in adults with spina bifida using the Health Facts data set: implications for transition planning and the development of adult clinics.

OBJECTIVE: As the care of patients with spina bifida continues to evolve, life expectancy is increasing, leading to a critical need for transition planning from pediatric-based to adult-based care. The burden of neurosurgical care for adults with spina bifida remains unknown. In this study, the authors sought to use a large national data set to estimate the prevalence of neurosurgical interventions in adults with spina bifida. METHODS: This study utilized Health Facts, which is a de-identified proprietary data set abstracted from all Cerner electronic health records. It includes 69 million unique patients with > 500 million encounters in 580 centers. Validation, technical exclusions, and data filters were applied to obtain an appropriate cohort of patients. The ICD-9 and ICD-10 codes for all types of spinal dysraphism, as well as the Current Procedural Terminology (CPT) codes for hydrocephalus procedures, spinal cord untethering, and Chiari decompression, were queried and records were retrieved. Demographic variables along with differences in age groups and temporal trends were analyzed. RESULTS: Overall, 24,764 unique patients with ≥ 1 encounter with a spinal dysraphism diagnosis between 2000 and 2017 were identified. The pediatric cohort included 11,123 patients with 60,027 separate encounters, and the adult cohort included 13,641 patients with 41,618 separate encounters. The proportion of females was higher in the adult (62.9%) than in the pediatric (51.4%) cohort. Annual encounters were stable from 2 to 18 years of age, but then decreased by approximately half with a precipitous drop after age 21 years. The sex distribution of adults and children who underwent procedures was similar (54.6% female adults vs 52.4% female children). Surgical interventions in adults were common. Between 2013 and 2017, there were 4913 procedures for hydrocephalus, with 2435 (49.6%) adult patients. Similarly, 273 (33.3%) of the 819 tethered cord procedures were performed in adults, as were 307 (32.9%) of 933 Chiari decompressions. CONCLUSIONS: The Health Facts database offered another option for studying care delivery and utilization in patients aging with spina bifida. The median age of this population has now reached early adulthood, and a significant number of neurosurgical procedures were performed in adults. An abrupt drop in the rate of encounters occurred at 21 years of age, possibly reflecting transition issues such as access-to-care problems and lack of coordinated care.

Demographics of children with feeding difficulties from a large electronic health record database.

BACKGROUND: Feeding difficulties are among the most common concerns expressed by parents in younger children. However, few studies have reported on the characteristics of patients with clinically significant feeding diagnoses. The aim of the current study is to describe the characteristics of patients diagnosed with feeding difficulties including concurrent conditions, age, and sex, sampled nationwide utilizing the Cerner Health Facts Database. METHODS: We identified patients with a diagnosis of feeding difficulties (ICD-9 783.3 or ICD-10 R63.3), age 7 months to 17 years, with an outpatient visit between 2010 and 2017. The demographics and complex clinical conditions of this population were categorized. The cohort was then collapsed into a matrix defining recognized phenotype codes for ICD-9 and ICD-10 diagnoses to identify associated conditions. RESULTS: We identified 39,674 patients (0.95%) representing 101,684 encounters from 68 health systems across the United States; 43% of patients were female. Gastrointestinal conditions were the most common, followed by malnutrition, developmental and behavioral diagnoses, and neurologic conditions. CONCLUSIONS: This study is one of the most robust studies defining the prevalence, demographic characteristics, and phenotypic profiling of patients with feeding difficulties. Our observations have implications on screening and resource allocation to recognize and manage this poorly understood population.

Small sleepers, big data: leveraging big data to explore sleep-disordered breathing in infants and young children.

STUDY OBJECTIVES: Infants represent an understudied minority in sleep-disordered breathing (SDB) research and yet the disease can have a significant impact on health over the formative years of neurocognitive development that follow. Herein we report data on SDB in this population using a big data approach. METHODS: Data were abstracted using the Cerner Health Facts database. Demographics, sleep diagnoses, comorbid medication conditions, healthcare utilization, and economic outcomes are reported. RESULTS: In a cohort of 68.7 million unique patients, over a 9-year period, there were 9,773 infants and young children with a diagnosis of SDB (obstructive sleep apnea [OSA], nonobstructive sleep apnea, and "other" sleep apnea) who met inclusion criteria, encompassing 17,574 encounters, and a total of 27,290 diagnoses across 62 U.S. health systems, 172 facilities, and 3 patient encounter types (inpatient, clinic, and outpatient). Thirty-nine percent were female. Thirty-nine percent were ≤1 year of age (6,429 infants), 50% were 1-2 years of age, and 11% were 2 years of age. The most common comorbid diagnoses were micrognathia, congenital airway abnormalities, gastroesophageal reflux, chronic tonsillitis/adenoiditis, and anomalies of the respiratory system. Payor mix was dominated by government-funded entities. CONCLUSIONS: We have used a novel resource, large-scale aggregate, de-identified EHR data, to examine SDB. In this population, SDB is multifactorial, closely linked to comorbid medical conditions and may contribute to a significant burden of healthcare costs. Further research focusing on infants at highest risk for SDB can help target resources and facilitate personalized management.

Clinical Outcome and Antibiotic Dosing Differences by Weight in Children With Acute Osteomyelitis.

OBJECTIVES: To evaluate for weight-based differences in clinical outcomes and antibiotic dosing variability for children hospitalized with acute hematogenous osteomyelitis (AHO). METHODS: We performed a retrospective cohort study of children aged 2 to 17 years and hospitalized with a primary AHO International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision diagnosis code between 2010 and 2017 using the Cerner Health Facts database. Weight categories (healthy, overweight, obesity) were determined by using Centers for Disease Control and Prevention age- and sex-specific BMI percentiles. Rates of procedures, complications, and length of stay (LOS) were compared between groups. Dosing variability between groups was assessed by comparing the initial milligrams per kilogram per day of prescribed antibiotics. RESULTS: We identified 755 children with AHO for inclusion. Children with overweight and obesity were more likely to undergo surgical procedures (19% and 17%, respectively) compared with children with a healthy weight (10%; P = .009). They also had a longer LOS (5.7 and 5.8 days) than children with a healthy weight (4.9 days; P = .03). There were no differences in complication rates between weight categories. Mean weight-adjusted daily dose for the most frequently prescribed antibiotics was different by weight category, with children in higher weight categories more likely to receive lower weight-based doses. CONCLUSIONS: Children with overweight and obesity hospitalized for AHO were more likely to undergo procedures, have longer LOS, and receive lower weight-based antibiotic dosing compared with children with a healthy weight. Our findings suggest that weight should be carefully considered when treating children with AHO.

Healthcare System-to-System Cost Variability in the Care of Pediatric Abdominal Pain-Associated Functional Gastrointestinal Disorders.

The purpose of this study was to assess cost variability in the care of abdominal pain-associated functional gastrointestinal disorders (AP-FGIDS) in youth across health systems, races, and specific AP-FGID diagnoses. Patients, aged 8-17 years, with a priority 1 diagnosis corresponding to a Rome IV defined AP-FGID were identified within the Health Facts® database. Total costs were obtained across the continuum of care including outpatient clinics, emergency department, and inpatient or observation units. Cost variability was described comparing different health systems, races, and diagnoses. Thirteen thousand two hundred and fourteen patients were identified accounting for 17,287 encounters. Total costs were available for 38.7% of the encounters. There was considerable variability in costs within and, especially, across health systems. Costs also varied across race, urban vs. rural site of care, and AP-FGID diagnoses. In conclusion, there was considerable variability in the costs for care of AP-FGIDs which is sufficient to support multi-site studies to understand the value of specific tests and treatments. Significant differences in costs by race merit further investigation to understand key drivers.

Obesity and Corticosteroid Dosing Guideline Adherence in Children Hospitalized With Asthma.

OBJECTIVES: Drug dosing recommendations for children with obesity remain limited. This may lead to variability in medication dosing among children with obesity. Therefore, our objective was to determine differences in the prevalence of guideline-nonadherent systemic corticosteroid orders by weight category in children hospitalized for asthma. METHODS: We performed a retrospective cross-sectional study of children aged 2 to 17 years hospitalized with asthma and prescribed systemic corticosteroids between January 1, 2010, and December 31, 2017, using the Cerner Health Facts deidentified database. Weight categories ranging from underweight to class III obesity were defined on the basis of BMI percentiles by using CDC guidelines. Corticosteroid orders were categorized as guideline adherent or nonadherent on the basis of total body weight-based dosing guidelines from the National Heart, Lung, and Blood Institute. χ2 test and multivariable logistic regression models were used to determine differences in guideline adherence between weight categories. RESULTS: We identified 21 488 children prescribed systemic corticosteroids during asthma hospitalizations. Most (54.2%) had a healthy weight, and 23.8% had obesity. Almost one-quarter received guideline-nonadherent orders (22.2%), with increasing prevalence among higher weight categories (19.4% of healthy weight children versus 36.0% of those with class III obesity; P < .001). After controlling for demographic and clinical covariates, weight category remained significantly associated with receiving a guideline-nonadherent order (P < .001). CONCLUSIONS: The prevalence of guideline-nonadherent corticosteroid orders for children hospitalized with asthma increases linearly with weight category, disproportionately affecting children with severe obesity. Standardization of drug dosing guidelines for children with obesity may help reduce variability in drug doses prescribed that may increase risk of harm.

Aligning EHR Data for Pediatric Leukemia With Standard Protocol Therapy.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) are treated according to risk-based protocols defined by the Children's Oncology Group (COG). Alignment between real-world clinical practice and protocol milestones is not widely understood. Aggregate deidentified electronic health record (EHR) data offer a useful resource to evaluate real-world clinical practice. METHODS: A cohort of children with ALL was identified in the Cerner Health Facts deidentified aggregate EHR data. Manual review identified candidate procedural milestones. Automated methods were developed to classify likely standard-risk precursor B-cell ALL patients. Milestone procedures were adjusted relative to initiation of therapy and then aligned to the COG protocols for standard induction therapy. RESULTS: We identified 7,728 patients with pediatric ALL with 188,187 encounters. Records for lumbar punctures (LP) and bone marrow biopsies were frequently present in the data and were appropriate targets to evaluate guideline performance. Alluvial graph analysis of 14 health systems indicated that none of the systems have data from all three COG-recommended lumbar procedures for all patients but alignment demonstrated that most systems test at the recommended times. CONCLUSION: Source-system variation introduces inconsistency and incompleteness into aggregate EHR data. Data visualization was helpful in characterizing and interpreting the data. Health systems with patients meeting the inclusion criteria demonstrated strong alignment with the recommended milestones for LP. Large-scale aggregate EHR data are useful to evaluate alignment of recommended versus actual clinical milestones in support of treating children with ALL. This work can inform other guideline and protocol driven care.

Big Data in Transplantation Practice-the Devil Is in the Detail-Fontan-associated Liver Disease.

BACKGROUND: As a result of the Fontan procedure, the prognosis of congenital single-ventricle heart disease has improved, with many affected children surviving into adulthood. However, the unanticipated consequences of chronic exposure to Fontan hemodynamics have revealed a new set of secondary noncardiac complications. Fontan-associated liver disease (FALD) is characterized by progressive hepatic fibrosis in nearly all patients post-Fontan, with the potential to develop cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A lack of data regarding FALD-related prognosis makes consideration of indications for and timing of heart alone versus combined heart-liver transplantation challenging. METHODS: A multidisciplinary group within the American Society for Transplantation analyzed several administrative datasets to study the epidemiology of FALD. RESULTS: This approach presented several obstacles, and efforts to characterize FALD were limited by a lack of Fontan- and FALD-specific diagnostic codes and an inability to follow individual patients through multiple health systems. Several ongoing Fontan registries were also reviewed but these do not adequately capture FALD-related variables. Such barriers highlight the need for large-scale data collection in patients post-Fontan to better understand and care for this complex population. CONCLUSIONS: This study emphasizes the challenges of studying emerging transplant-related diagnoses in existing datasets and the need for mechanisms to adapt registries to appropriately identify patients with rare or emerging conditions.

Heterogeneity introduced by EHR system implementation in a de-identified data resource from 100 non-affiliated organizations.

OBJECTIVES: Electronic health record (EHR) data aggregated from multiple, non-affiliated, sources provide an important resource for biomedical research, including digital phenotyping. Unlike work with EHR data from a single organization, aggregate EHR data introduces a number of analysis challenges. MATERIALS AND METHODS: We used the Cerner Health Facts data, a de-identified aggregate EHR data resource populated by data from 100 independent health systems, to investigate the impact of EHR implementation factors on the aggregate data. These included use of ancillary modules, data continuity, International Classification of Disease (ICD) version and prompts for clinical documentation. RESULTS AND DISCUSSION: Health Facts includes six categories of data from ancillary modules. We found of the 664 facilities in Health Facts, 49 use all six categories while 88 facilities were not using any. We evaluated data contribution over time and found considerable variation at the health system and facility levels. We analyzed the transition from ICD-9 to ICD-10 and found that some organizations completed the shift in 2014 while others remained on ICD-9 in 2017, well after the 2015 deadline. We investigated the utilization of "discharge disposition" to document death and found inconsistent use of this field. We evaluated clinical events used to document travel status implemented in response to Ebola, height and smoking history. Smoking history documentation increased dramatically after Meaningful Use, but dropped in some organizations. These observations highlight the need for any research involving aggregate EHR data to consider implementation factors that contribute to variability in the data before attributing gaps to "missing data."

Genome-wide mapping of the cohesin complex in the yeast Saccharomyces cerevisiae.

In eukaryotic cells, cohesin holds sister chromatids together until they separate into daughter cells during mitosis. We have used chromatin immunoprecipitation coupled with microarray analysis (ChIP chip) to produce a genome-wide description of cohesin binding to meiotic and mitotic chromosomes of Saccharomyces cerevisiae. A computer program, PeakFinder, enables flexible, automated identification and annotation of cohesin binding peaks in ChIP chip data. Cohesin sites are highly conserved in meiosis and mitosis, suggesting that chromosomes share a common underlying structure during different developmental programs. These sites occur with a semiperiodic spacing of 11 kb that correlates with AT content. The number of sites correlates with chromosome size; however, binding to neighboring sites does not appear to be cooperative. We observed a very strong correlation between cohesin sites and regions between convergent transcription units. The apparent incompatibility between transcription and cohesin binding exists in both meiosis and mitosis. Further experiments reveal that transcript elongation into a cohesin-binding site removes cohesin. A negative correlation between cohesin sites and meiotic recombination sites suggests meiotic exchange is sensitive to the chromosome structure provided by cohesin. The genome-wide view of mitotic and meiotic cohesin binding provides an important framework for the exploration of cohesins and cohesion in other genomes.

A flexible template boundary element in the RNA subunit of fission yeast telomerase.

Telomerase adds telomeric repeat sequences to chromosome ends using a short region of its RNA subunit as a template. Telomerase RNA subunits are phylogenetically highly divergent, and different strategies have evolved to demarcate the boundary of the template region. The recent identification of the gene encoding telomerase RNA in the fission yeast Schizosaccharomyces pombe (ter1+) has opened the door for structure-function analyses in a model that shares many features with the telomere maintenance machinery of higher eukaryotes. Here we describe a structural element in TER1 that defines the 5' boundary of the template. Disruption of a predicted long range base pairing interaction between template-adjacent nucleotides and a sequence further upstream resulted in reverse transcription beyond the template region and caused telomere shortening. Normal telomere length was restored by combining complementary nucleotide substitutions in both elements, showing that base pairing, not a specific sequence, limits reverse transcription beyond the template. The template boundary described here resembles that of budding yeasts and some mammalian telomerases. However, unlike any previously characterized boundary element, part of the paired region overlaps with the template itself, thus necessitating disruption of these interactions during most reverse transcription cycles. We show that changes in the paired region directly affect the length of individual telomeric repeat units. Our data further illustrate that marginal alignment of the telomeric 3' end with RNA sequences downstream of the template is responsible for primer slippage, causing incorporation of strings of guanosines at the start of a subset of repeats.

Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function.

Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.

Comparison of pattern detection methods in microarray time series of the segmentation clock.

While genome-wide gene expression data are generated at an increasing rate, the repertoire of approaches for pattern discovery in these data is still limited. Identifying subtle patterns of interest in large amounts of data (tens of thousands of profiles) associated with a certain level of noise remains a challenge. A microarray time series was recently generated to study the transcriptional program of the mouse segmentation clock, a biological oscillator associated with the periodic formation of the segments of the body axis. A method related to Fourier analysis, the Lomb-Scargle periodogram, was used to detect periodic profiles in the dataset, leading to the identification of a novel set of cyclic genes associated with the segmentation clock. Here, we applied to the same microarray time series dataset four distinct mathematical methods to identify significant patterns in gene expression profiles. These methods are called: Phase consistency, Address reduction, Cyclohedron test and Stable persistence, and are based on different conceptual frameworks that are either hypothesis- or data-driven. Some of the methods, unlike Fourier transforms, are not dependent on the assumption of periodicity of the pattern of interest. Remarkably, these methods identified blindly the expression profiles of known cyclic genes as the most significant patterns in the dataset. Many candidate genes predicted by more than one approach appeared to be true positive cyclic genes and will be of particular interest for future research. In addition, these methods predicted novel candidate cyclic genes that were consistent with previous biological knowledge and experimental validation in mouse embryos. Our results demonstrate the utility of these novel pattern detection strategies, notably for detection of periodic profiles, and suggest that combining several distinct mathematical approaches to analyze microarray datasets is a valuable strategy for identifying genes that exhibit novel, interesting transcriptional patterns.

Detecting periodic patterns in unevenly spaced gene expression time series using Lomb-Scargle periodograms.

MOTIVATION: Periodic patterns in time series resulting from biological experiments are of great interest. The commonly used Fast Fourier Transform (FFT) algorithm is applicable only when data are evenly spaced and when no values are missing, which is not always the case in high-throughput measurements. The choice of statistic to evaluate the significance of the periodic patterns for unevenly spaced gene expression time series has not been well substantiated. METHODS: The Lomb-Scargle periodogram approach is used to search time series of gene expression to quantify the periodic behavior of every gene represented on the DNA array. The Lomb-Scargle periodogram analysis provides a direct method to treat missing values and unevenly spaced time points. We propose the combination of a Lomb-Scargle test statistic for periodicity and a multiple hypothesis testing procedure with controlled false discovery rate to detect significant periodic gene expression patterns. RESULTS: We analyzed the Plasmodium falciparum gene expression dataset. In the Quality Control Dataset of 5080 expression patterns, we found 4112 periodic probes. In addition, we identified 243 probes with periodic expression in the Complete Dataset, which could not be examined in the original study by the FFT analysis due to an excessive number of missing values. While most periodic genes had a period of 48 h, some had a period close to 24 h. Our approach should be applicable for detection and quantification of periodic patterns in any unevenly spaced gene expression time-series data.