Sociodemographic structure and health care-related outcomes of community-dwelling dementia caregiving dyads: a latent class replication study.

BACKGROUND: The identification of dyadic subgroups of individuals living with dementia and their informal caregivers can help to design effective tailored support. In a previous German study, we identified six dementia dyad subgroups by applying Latent Class Analysis (LCA). Results showed sociodemographic heterogeneity as well as differences in health care outcomes (i.e., quality of life, health status, caregiver burden) between subgroups. The objective of this study is to determine if the dyad subgroups from the previous analysis can be replicated in a similar but distinct Dutch sample. METHODS: A LCA 3-step procedure was applied to baseline data from the COMPAS study, a prospective cohort study. LCA is a statistical approach used to identify heterogeneous subgroups within populations based on their pattern of answers on a set of categorical variables. Data comprises 509 community-living individuals with predominantly mild to moderate dementia and their informal caregivers. A narrative analysis was used to compare latent class structures of the original versus the replication study. RESULTS: Six distinct dementia dyad subgroups were identified: A subgroup of "adult-child-parent relation with younger informal caregiver" (31.8%), a "couple with female informal caregiver of older age" group (23.1%), an "adult-child-parent relation with middle-aged informal caregiver" group (14.2%), a "couple with middle-aged female informal caregiver" group (12.4%), a "couple with older male informal caregiver" group (11.2%) and a "couple with middle-aged male informal caregiver" group (7.4%). Quality of life of individuals with dementia was rated better in couples than in adult-child-relationships. Worst health for caregivers was reported by subgroups with female informal caregivers living together with male individuals with dementia in couple relationships. A subgroup with older female informal caregivers in couple relationships report the most severe burden on physical and mental health. In both studies, a model with six subgroups fitted the data best. Although substantive similarities between the subgroups of both studies appeared, considerable differences are also evident. CONCLUSION: This replication study confirmed the existence of informal dementia dyad subgroups. The observed differences between the subgroups provide useful contributions for a more tailored health care services for informal caregivers and individuals living with dementia. Furthermore, it underlines the relevance of dyadic perspectives. To facilitate replication studies and increase the validity of evidence, a standardization of collected data across studies would be beneficial.

Comparison of age- and sex-dependent reference limits derived from distinct sources for metabolic measurands in basic liver diagnostics.

BACKGROUND: Reference intervals for basic liver laboratory diagnostic rely on manufacturers' information, remaining unchanged for more than 20 years. This ignores known age and sex dependencies. METHODS: We performed a retrospective cross-sectional study to compare the age-dependent distribution of flagged and non-flagged laboratory findings between reference limits from 3 distinct sources: manufacturer, published reference study, and the truncated maximum likelihood method applied on a cohort of inpatients aged 18-100 years. Discordance rates adjusted for the permissible analytical uncertainty are reported for serum levels of albumin (n= 150,550), alkaline phosphatase (n= 433,721), gamma-GT (n=580,012), AST (n= 510,620), and ALT (n= 704,546). RESULTS: The number of flagged findings differed notably between reference intervals compared, except for alkaline phosphatase. AST and alkaline phosphatase increased with age in women. Overall discordance for AP, AST, and ALT remained below 10%, respectively, in both sexes. Albumin decreased with age which led to discordant flags in up to 22% in patients ≥70 years. GGT and ALT peaked in 50-59-year-old men with up to 23.5% and 22.8% discordant flags, respectively. CONCLUSION: We assessed the impact of different reference limits on liver related laboratory results and found up to 25 % discordant flags. We suggest to further analyse the diagnostic and economic effects of reference limits adapted to the population of interest even for well-established basic liver diagnostics.

Comparison of Mortality Prediction Scores in Intermediate-Care Patients with Liver Cirrhosis at a German University Transplant Centre: A Prospective Study.

BACKGROUND AND AIMS: Mortality prediction models help to extract and relate patient data upon admission to intensive or intermediate care units (ImCUs). Considering technical and economic healthcare developments, re-evaluations of score performances are required to warrant their validity. This study validates and compares established scoring systems in cirrhotic ImCU patients. METHODS: Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) 2 and 3, Sepsis Organ Failure Assessment (SOFA), Mortality Probability Model at ICU admission (MPMo) II and III, Model for End stage Liver Disease (MELD), CLIF-Consortium Acute-on-Chronic Liver Failure (CLIF-C ACLF), CLIF-Consortium Acute Decompensation (CLIF-C AD), and Intermediate Care Unit Severity Score (ImCUSS) were calculated in patients with cirrhosis (n = 98) at ImCU admission. Discrimination performances were evaluated by area under the receiver operating characteristic curves (AUROCs), calibration performances with calibration belt plots, and their corresponding p values. RESULTS: Overall, SAPS 3 and CLIF-C ACLF have shown the best 90-day mortality prediction outcomes with AUROCs of 0.825 and 0.783 along with calibration belt p values of 0.128 and 0.061, respectively. In a subgroup analysis of patients with acute-on-chronic liver failure (ACLF), expanded SAPS 2, SOFA, and SAPS 3 reached the best AUROCs, i.e., 0.760, 0.750, and 0.714, but none of the tested scores reached an acceptable calibration. CONCLUSION: Ninety-day mortality risk prediction of the SAPS 3 and CLIF-C ACLF was accurate in our cohort of patients with liver cirrhosis admitted to ImCUs. A particular challenge remains that is the mortality prediction in patients with ACLF requiring ImCU-level care; here, further developments are needed to generate scores with acceptable predictive performances.

Sociodemographic aspects and health care-related outcomes: a latent class analysis of informal dementia care dyads.

BACKGROUND: Studies revealed the importance to assess dementia care dyads, composed of persons with dementia and their primary informal caregivers, in a differentiated way and to tailor support services to particular living and care circumstances. Therefore, this study aims first to identify classes of dementia care dyads that differ according to sociodemographic, care-related and dementia-specific characteristics and second, to compare these classes with regard to healthcare-related outcomes. METHODS: We used data from the cross-sectional German DemNet-D study (n = 551) and conducted a latent class analysis to investigate different classes of dementia care dyads. In addition, we compared these classes with regard to the use of health care services, caregiver burden (BIZA-D), general health of the informal caregiver (EQ-VAS) as well as quality of life (QoL-AD) and social participation (SACA) of the person with dementia. Furthermore, we compared the stability of the home-based care arrangements. RESULTS: Six different classes of dementia care dyads were identified, based on best Bayesian Information Criterion (BIC), significant likelihood ratio test (p <  0.001), high entropy (0.87) and substantive interpretability. Classes were labelled as "adult child parent relationship & younger informal caregiver", "adult child parent relationship & middle aged informal caregiver", "non family relationship & younger informal caregiver", "couple & male informal caregiver of older age", "couple & female informal caregiver of older age", "couple & younger informal caregiver". The classes showed significant differences regarding health care service use. Caregiver burden, quality of life of the person with dementia and stability of the care arrangement differed also significantly between the classes. CONCLUSION: Based on a latent class analysis this study indicates differences between classes of informal dementia care dyads. The findings may give direction for better tailoring of support services to particular circumstances to improve healthcare-related outcomes of persons with dementia and informal caregivers.

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic).

Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when <20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital's laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic.

Next-generation reference intervals for pediatric hematology.

Background Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. Methods We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905-1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. Results We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. Conclusions The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.

Indirect determination of hematology reference intervals in adult patients on Beckman Coulter UniCell DxH 800 and Abbott CELL-DYN Sapphire devices.

Background Conventional establishment of reference intervals for hematological analytes is challenging due to the need to recruit healthy persons. Indirect methods address this by deriving reference intervals from clinical laboratory databases which contain large datasets of both physiological and pathological test results. Methods We used the "Reference Limit Estimator" (RLE) to establish reference intervals for common hematology analytes in adults aged 18-60 years. One hundred and ninety-five samples from 44,519 patients, measured on two different devices in a tertiary care center were analyzed. We examined the influence of patient cohorts with an increasing proportion of abnormal test results, compared sample selection strategies, explored inter-device differences, and analyzed the stability of reference intervals in simulated datasets with varying overlap of pathological and physiological test results. Results Reference intervals for hemoglobin, hematocrit, red cell count and platelet count remained stable, even if large numbers of pathological samples were included. Reference intervals for red cell indices, red cell distribution width and leukocyte count were sufficiently stable, if patient cohorts with the highest fraction of pathological samples were excluded. In simulated datasets, estimated reference limits shifted, if the pathological dataset contributed more than 15%-20% of total samples and approximated the physiological distribution. Advanced sample selection techniques did not improve the algorithm's performance. Inter-device differences were small except for red cell distribution width. Conclusions The RLE is well-suited to create reference intervals from clinical laboratory databases even in the challenging setting of a adult tertiary care center. The procedure can be used as a complement for reference interval determination where conventional approaches are limited.

Critical comments to a recent EFLM recommendation for the review of reference intervals.

In a recent EFLM recommendation on reference intervals by Henny et al., the direct approach for determining reference intervals was proposed as the only presently accepted "gold" standard. Some essential drawbacks of the direct approach were not sufficiently emphasized, such as unacceptably wide confidence limits due to the limited number of observations claimed and the practical usability for only a limited age range. Indirect procedures avoid these disadvantages of the direct approach. Furthermore, indirect approaches are well suited for reference limits with large variations during lifetime and for common reference limits.

Pediatric reference intervals for alkaline phosphatase.

BACKGROUND: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. METHODS: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method. RESULTS: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. CONCLUSIONS: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.

Age- and sex-specific dynamics in 22 hematologic and biochemical analytes from birth to adolescence.

BACKGROUND: Pediatric laboratory test results must be interpreted in the context of interindividual variation and age- and sex-dependent dynamics. Reference intervals as presently defined for separate age groups can only approximate the age-related dynamics encountered in pediatrics. Continuous reference intervals from birth to adulthood are not available for most laboratory analytes because of the ethical and practical constraints of defining reference intervals using a population of healthy community children. We applied an indirect method to generate continuous reference intervals for 22 hematologic and biochemical analytes by analyzing clinical laboratory data from blood samples taken during clinical care of patients. METHODS: We included samples from 32 000 different inpatients and outpatients (167 000 samples per analyte) from a German pediatric tertiary care center. Measurements were performed on a Sysmex-XE 2100 and a Cobas Integra 800 during clinical care over a 6-year period. The distribution of samples considered normal was estimated with an established indirect statistical approach and used for the calculation of reference intervals. RESULTS: We provide continuous reference intervals from birth to adulthood for 9 hematology analytes (hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count, and platelet count) and 13 biochemical analytes (sodium, chloride, potassium, calcium, magnesium, phosphate, creatinine, aspartate transaminase, alanine transaminase, γ-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, and total protein). CONCLUSIONS: Continuous reference intervals capture the population changes in laboratory analytes during pediatric development more accurately than age groups. After local validation, the reference intervals provided should allow a more precise consideration of these dynamics in clinical decision making.

Indirect determination of pediatric blood count reference intervals.

BACKGROUND: Determination of pediatric reference intervals (RIs) for laboratory quantities, including hematological quantities, is complex. The measured quantities vary by age, and obtaining samples from healthy children is difficult. Many widely used RIs are derived from small sample numbers and are split into arbitrary discrete age intervals. Use of intra-laboratory RIs specific to the examined population and analytical device used is not yet fully established. Indirect methods address these issues by deriving RIs from clinical laboratory databases which contain large datasets of both healthy and pathological samples. METHODS: A refined indirect approach was used to create continuous age-dependent RIs for blood count quantities and sodium from birth to adulthood. The dataset for each quantity consisted of 60,000 individual samples from our clinical laboratory. Patient samples were separated according to age, and a density function of the proportion of healthy samples was estimated for each age group. The resulting RIs were merged to obtain continuous RIs from birth to adulthood. RESULTS: The obtained RIs were compared to RIs generated by identical laboratory instruments, and to population-specific RIs created using conventional methods. This comparison showed a high concordance of reference limits and their age-dependent dynamics. CONCLUSIONS: The indirect approach reported here is well-suited to create continuous, intra-laboratory RIs from clinical laboratory databases and showed that the RIs generated are comparable to those created using established methods. The procedure can be transferred to other laboratory quantities and can be used as an alternative method for RI determination where conventional approaches are limited.

Indirect reference intervals of plasma and serum thyrotropin (TSH) concentrations from intra-laboratory data bases from several German and Italian medical centres.

BACKGROUND: The dogma of establishing intra-laboratory reference limits (RLs) and their periodic review cannot be fulfilled by most laboratories due to the expenses involved. Thus, most laboratories adopt external sources for their RLs, often neglecting the problems of transferability. This is particularly problematic for analytes with a large diversity of existing RLs, as for example thyrotropin (TSH). Several attempts were taken to derive RLs from the large data pools stored in modern laboratory information systems. These attempts were further developed to a more sophisticated indirect procedure. The new approach can be considered a combined concept because it pre-excludes some subjects by direct criteria a-posterior. In the current study, the applicability of the new concept for modern protein bindings assays was examined for estimating RLs of serum and plasma TSH with data sets from several German and Italian laboratories. METHODS: A smoothed kernel density function was estimated for the distribution of the total mixed data of the sample group (combined data of non-diseased and diseased subjects). It was assumed that the "central" part of the distribution of all data represents the non-diseased ("healthy") population. The central part was defined by truncation points using an optimisation method, and was used to estimate a Gaussian distribution of the values of presumably non-diseased subjects after Box-Cox transformation of the empirical data. This distribution was now considered as the distribution of the non-diseased subgroup. The percentiles of this parametrical distribution were calculated to obtain RLs. RESULTS: RLs determined by the indirect combined decomposition technique led to similar RLs as found by several recent study reports using a direct method according to international recommendations. Furthermore, the RLs obtained from 13 laboratories in two different European regions reflected the well-known differences of various analytical procedures. Stratification for gender and age was necessary in contrast to earlier reports. With increasing age, an increase of the upper RL and the reference range was observed. Hospitalisation also affected the RLs. Common RLs appeared acceptable only within the same analytical systems. Some laboratories used RLs which were not appropriate for the population served. CONCLUSIONS: The proposed strategy of combining exclusion criteria with a resolution technique led to retrospective RLs from intra-laboratory data pools for TSH which were comparable with directly determined RLs. Differences between laboratories were due primarily to the well-known bias of the different analytical procedures and to the status of the population.

Reference limits of plasma and serum creatinine concentrations from intra-laboratory data bases of several German and Italian medical centres: Comparison between direct and indirect procedures.

BACKGROUND: The current dogma of establishing intra-laboratory reference limits (RLs) and their periodical reviewing cannot be fulfilled by most laboratories due to the expenses involved. Thus, most laboratories adopt external sources for their RLs often neglecting the problems of transferability. Therefore, several attempts were undertaken to derive RLs from the large data pools stored in modern laboratory information systems. These attempts were further developed to a more sophisticated indirect procedure. The new model can be considered a combined approach because it pre-excludes some subjects by direct criteria. In the current study, the new concept was applied to estimate RLs for serum and plasma creatinine from several German and Italian laboratories. METHODS: A smoothed kernel density function was estimated for the distribution of the total mixed data of the sample group (combined data of non-diseased and diseased subjects). It was assumed that the "central" part of the distribution of all data represents the non-diseased ("healthy") population. The central part was defined by truncation points using an optimisation method, and was used to estimate a Gaussian distribution of the values of presumably non-diseased subjects after Box-Cox transformation of the empirical data. This distribution was now considered as the distribution of the non-diseased subgroup. The percentiles of this parametrical distribution were calculated to obtain RLs. RESULTS: RLs determined by the indirect combined decomposition technique led to similar RLs as the classical direct method. Furthermore, the RLs obtained from 14 laboratories in 2 different European regions reflected the well-known differences of various analytical procedures. Stratification for gender and age was necessary. With rising age, an increase of the upper RL and of the reference range was observed. Hospitalization appeared also to affect the RLs. The new approach led to RLs in an artificially mixed population of diseased and non-diseased subjects (selected by clinical criteria) which were identical to RLs determined by a direct method applied to the non-diseased subgroup. CONCLUSIONS: The proposed strategy of combining exclusion criteria with a resolution technique led to plausible retrospective RLs from intra-laboratory data pools for creatinine. Differences between laboratories were mainly due to the well-known bias of the different analytical procedures.

A plea for intra-laboratory reference limits. Part 1. General considerations and concepts for determination.

Accurate results for quantitative procedures can be useless if the reference limits for the interpretation of laboratory results are unreliable. Recent concepts for quality management systems require that laboratories pay more attention to identification and verification of reference limits. Scientific recommendations often claim that each laboratory should determine intra-laboratory reference limits, which should be reviewed periodically. This recommendation is currently neglected by most laboratories; instead they use reference limits from external sources, despite various problems of transference. Prospective and retrospective methods either using or neglecting disease prevalences (polymodal or unimodal concepts, respectively) and applying different statistical approaches for determining reference limits have been described. The various procedures are reviewed with regard to their diagnostic sensitivity, specificity and (non-)efficiency. The present gold standard is the reference limit concept according to IFCC recommendations (a unimodal prospective approach). This concept, together with trueness-based standardization, is the most useful basis for harmonization of the decision-making process with laboratory results, despite complex problems of traceability and transference. This harmonization is at present only achieved for a limited number of analytes for which SI units and traceability can be technically realized. For the majority of measurands in laboratory medicine, much research is still required and results cannot be expected in the near future. For these measurands, a need remains for internal, efficient and simple identification of population-based reference limits. Therefore, newer retrospective concepts were developed that use large data sets from laboratory information systems to derive intra-laboratory reference limits. These approaches appear promising and should be further developed.

A plea for intra-laboratory reference limits. Part 2. A bimodal retrospective concept for determining reference limits from intra-laboratory databases demonstrated by catalytic activity concentrations of enzymes.

BACKGROUND: The current recommendations for establishing intra-laboratory reference limits (RLs) cannot be fulfilled by most laboratories because of the expense involved. In the current study, a bimodal method was developed to derive RLs from data stored in a laboratory information system without any assumption concerning the distribution of the diseased subgroup. METHODS: A smoothed kernel density function (D(mix)) was estimated for the distribution of combined data for non-diseased and diseased adult subjects. It was assumed that the "central" part of the distribution represents the non-diseased population, which was defined and used to estimate a Gaussian distribution of either the original values or Box-Cox transformed data. This normal distribution was now considered the distribution of the non-diseased subgroup (D(nd)). Percentiles were calculated to obtain retrospective RLs. The density function of the diseased subgroup (D(d)) was calculated by subtracting the non-diseased density function from D(mix) (D(d)=D(mix)-D(nd)). The intersection point of the D(nd) and D(d) curves identified the RL with the highest diagnostic efficiency. RESULTS: The model was applied to catalytic activity concentrations of several enzymes with data from different laboratories. The RLs obtained were similar to recently published consensus values. Differences between laboratories were small but significant. Gender stratification was necessary for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutymaltransferse (gamma-GT), not significant for lipase and amylase and inconsistent among the laboratories for alkaline phosphatase (AP) and lactate dehydrogenase (LDH). Age stratification was only tested for two groups (18-49 and >or=50 years) and was significant for AST (females only), gamma-GT and lipase, not significant for amylase and inconsistent for AP, LDH and ALT. For gamma-GT, further stratification for age in decades was necessary for males. Creatine kinase MB (CK-MB) values were not stratified owing to the low number of data available. CONCLUSIONS: Retrospective RLs derived from intra-laboratory data pools for the catalytic activity concentration of enzymes using a modified procedure plausibly agreed with published consensus values. However, most RLs varied significantly among laboratories, thus supporting the "old" plea for intra-laboratory RLs.