Incremental Healthcare Costs of Diabetes Mellitus in a Middle-Income Country Using Administrative Healthcare Data.

OBJECTIVES: To estimate the incremental medical cost of diabetes mellitus using information from administrative databases in Colombia. METHODS: We carried out a retrospective cohort study with administrative health databases from Colombian population affiliated in the contributory health insurance scheme. We used an operative definition to select the cohort with diabetes. Incremental cost and cost ratio of diabetes were estimated using an inverse probability weighting of treatment approach to find the causal effect of having the disease. Weights were calculated by a propensity score method using a Random Forest model. The flexibility of this machine learning algorithm allows to have a better specification and bias reduction. Additionally, we reported incremental costs and cost ratios with confidence intervals using bootstrapping and analyzed costs by age groups and complications associated with diabetes. RESULTS: The estimated prevalence of diabetes was 2834 per 100 000 cases, in 2018. The group with diabetes was comprised 634 015 people and the control group 1 524 808. The calculated annual direct medical cost was $860, for which the incremental cost was $493 and the cost ratio 2.34. The incremental annual cost for some type of complication ranges from $1239 to $2043, renal complication being the most expensive. Incremental cost by age groups ranges from $347 to $878, being higher in younger people. CONCLUSIONS: Although the cost of diabetes in Colombia ranges among the global averages and is similar to other Latin-American countries, a greater incremental cost was found in patients with renal, circulatory, and neurologic complications.

[Faecal microbiota study reveals specific dysbiosis in spondyloarthritis according to subtype, disease activity and treatment]. / Estudio de microbiota fecal revela disbiosis específica en espondiloartritis, según subtipo, actividad de la enfermedad y tratamiento.

OBJECTIVE: To compare the diversity and composition of the gastrointestinal microbiome of patients with SpA. METHODS: MiSeq sequencing of the V3-V4 region of the 16S ribosomal RNA gene was performed on DNA isolated from stool. Patients with concurrent SpA and IBD were excluded. Differences were assessed for richness and diversity indices by QIIME 2™. Differences between means >0,2% with a p-value<0,05 were assumed significant. Institutional Ethics Committee endorsement. RESULTS: 69 individuals included, 49 with SpA (ankylosing spondylitis-AS 72,9%, psoriatic arthritis-PsA 18,8%, reactive arthritis-ReA 8,3%) 5 positive controls-dysbiosis and 15 controls-eubiosis. Conventional treatment in 42,9%, anti-IL-17 16,3% and anti-TNF 40,8%. By subtype, statistically significant differences in favour of AS were found for the diversity indices. AS vs PsA there was a difference in favour of AS for Clostridium clostridioforme (p=0,002), Gemmiger formicilis (p=0,009), Roseburia inulivorans (p=0,008) and Lachnospira pectinoschiza. AS vs ReA there was a difference in favour of AS for L. pectinoschiza (p=0,009), Ruminococcus callidus (p=0.006), Clostridium ruminantium (p=0.031); G. formicilis (p=0,034). Diversity and richness showed differences in patients with high activity for Simpson's and Pielou's indices. In high activity, lower enrichment of Bacteroides eggerthii (p= 0,0003), C. ruminantium (p= 0,026) and Alistipes putredinis (p=0,035) was found. The number of ASV was higher in the anti-IL-17 vs conventional group (p=0.025) and a trend between anti-IL-17 vs anti-TNF (p=0.09). In anti-TNF there was a lower proportion for C. clostridioforme (p=0.023), G. formicilis (p=0.030) and R. callidus (p= 0.003). In anti IL-17, Alistipes indistinctus (p= 0.012) was decreased. CONCLUSIONS: There are differences in microbial diversity for SpA subtypes. The level of disease activity is plausible to influence the composition of the faecal microbiota. Anti-TNFα treatment may influence the microbiome environment favouring restoration of the gut microbiota, while anti-IL-17 may maintain an inflammatory environment.

OBJETIVO: Comparar la diversidad y composición del microbioma gastrointestinal de pacientes con EspA. MÉTODOS: La secuenciación MiSeq de la región V3-V4 del gen ARN ribosomal 16, se realizó en ADN aislado de heces. Se excluyeron pacientes con EspA y EII simultánea. Se evaluaron diferencias para los índices de riqueza y diversidad por medio de QIIME 2™. Las diferencias entre medias> 0,2%, con un valor de p< 0,05, se asumieron significativas. Aval del Comité de Ética Institucional. RESULTADOS: 69 individuos incluidos, 49 con EspA (espondilitis anquilosante-EA 72,9%, artritis psoriásica-APs 18,8%, artritis reactiva-ARe 8,3%), cinco controles positivos-disbiosis y 15 controles-eubiosis. El tratamiento convencional en 42,9%, anti-IL-17 16,3%, y anti-TNF 40,8%. Por subtipo-EasP, se encontraron diferencias estadísticamente significativas a favor de EA para los índices de diversidad. Entre EA vs APs, hubo diferencia a favor de EA para Clostridium clostridioforme (p=0,002), Gemmiger formicilis (p=0,009), Roseburia inulivorans (p=0,008) y Lachnospira pectinoschiza. Entre EA vs ARe hubo diferencia a favor de EA para L. pectinoschiza (p=0,009), Ruminococcus callidus (p = 0,006), Clostridium ruminantium (p=0,031); G. formicilis (p=0,034). La diversidad y riqueza mostraron diferencias en pacientes con alta actividad para los índices de Simpson y Pielou. En alta actividad, se encontró menor enriquecimiento de Bacteroides eggerthii (p=0,0003), C. ruminantium (p= 0,026) y Alistipes putredinis (p= 0,035). El número de ASV fue superior en el grupo de anti IL-17 vs convencional (p=0.025), y una tendencia entre anti IL-17 vs anti-TNF (p=0,09). En anti TNF hubo menor proporción para C. clostridioforme (p=0,023), G. formicilis (p=0,030) y R. callidus (p= 0,003). Y en anti IL-17, Alistipes indistinctus (p= 0,012), estuvo disminuida. CONCLUSIONES: Existen diferencias en la diversidad microbiana para los subtipos de EspA. El nivel de actividad de la enfermedad es plausible para influir en la composición de microbiota fecal. El tratamiento con anti-TNFα, puede influenciar el ambiente del microbioma favoreciendo la restauración de la microbiota intestinal, mientras los anti IL-17 podrían mantener un ambiente inflamatorio.

Implementation of screening criteria for inflammatory bowel disease in patients with spondyloarthritis and its association with disease and endoscopic activity.

There is little literature on the implementation of screening criteria for inflammatory bowel disease (IBD) in patients with spondyloarthritis (SpA). This study aimed to apply IBD screening criteria in a group of patients with SpA without IBD diagnosis and correlate them to endoscopic findings and disease activity. A total of 82 patients with SpA were included. The IBD screening test and ileocolonoscopy with digital chromoendoscopy with magnification and histological analysis were performed. The data were analysed with Chi-square test/Fisher's exact test and multiple correspondence analysis. The major screening criteria found in 48.7% of the patients were associated with a history of infection (p = 0.037). Rectal bleeding was associated with the diagnosis of ankylosing spondylitis, acute inflammation, enthesitis and tissue architecture alteration in the ileum (p < 0.050). Diarrhoea was associated with a higher disease activity score (p = 0.02). Minor screening criteria were associated with painful inflammatory joint (p = 0.05), high disease activity score (p = 0.001) and high calprotectin levels (p = 0.050). Abdominal pain (36.9%) was associated with axial/peripheral compromise (p = 0.017), inflammatory back pain (p = 0.01), enthesitis (p = 0.021), higher disease activity score (p = 0.023) and acute ileum inflammation (p = 0.046). Diarrhoea of 4 weeks and abdominal pain were the most prevalent major and minor screening criteria, respectively, being related to early manifestations of inflammatory bowel compromise and higher disease activity score. This screening test grants a chance of opportune referral of SpA patients from rheumatology to gastroenterology.

Oral manifestations associated with inflammatory bowel disease and early endoscopic findings in patients with spondyloarthritis.

BACKGROUND AND AIMS: Spondyloarthritis (SpA) is a group of autoinflammatory disorders, of which the primary extra-articular manifestation is inflammatory bowel disease (IBD). The oral cavity being a part of gastrointestinal tract, is significantly compromised in IBD, and in many cases, it is the first site of clinical manifestations of IBD. This study aimed to identify changes in the oral mucosa associated with the onset of IBD and their association with endoscopic/histological findings. MATERIALS AND METHODS: The study assessed 80 patients with SpA and 52 healthy controls. Oral, rheumatological, and gastroenterological assessments were performed. The ileocolonoscopy was performed via digital magnification chromoendoscopy. The statistical analysis consisted of Chi-square, Fisher's exact, and multiple correspondence discriminant analysis tests. RESULTS: From the disease cohort, 63.0% patients showed oral lesions (p = 0.050). These manifestations ranged from gingivitis (55.0%, p = 0.001), aphthous stomatitis (3.8%, p = 0.091), angular cheilitis (2.6%, p = 0.200), and perioral erythema with scaling (1.3%, p = 0.300). All patients who presented with alterations in colonic mucosa also had oral lesions associated with IBD (p = 0.039), specifically gingivitis/aphthous stomatitis (p = 0.029). CONCLUSION: The patients with SpA without IBD present significant oral signs and symptoms. Gingivitis seems to be the most relevant because of its associations with early endoscopic and histological findings. CLINICAL RELEVANCE: An integral approach to the diagnostic tests that includes evaluations of oral, rheumatological and gastroenterological tissues may favor timely attention and improve patients' quality of life.

Infection detection in patients with systemic lupus erythematosus using a hospital administrative database

Objective: To estimate the frequency of infections and to describe the pattern of these infections among patients diagnosed with Systemic Lupus Erythematous (SLE) treated at the Central Military Hospital (HOMIL). Methods: A descriptive study was carried out using an administrative database of the military hospital, we used a validated algorithm that classifies patients as having SLE in administrative databases. Infection was defined as an event with main diagnosis using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) coding algorithm or by searching the antibiotics prescription database, additionally, we abstracted some variables related to SLE status in the group of patients in whom infections were documented during the infection event. Results: 237 SLE patients were identified. The mean age was 41.9 years (CI 29.0-54.3), 80% were female, 97.7% used conventional disease-modifying anti-rheumatic drugs (DMARDs). Of these 237 patients, 22 (9.4%) met the operative definition of infection, in this group the mean age was 44.3 years (SD 16.4). All the 22 patients received conventional DMARDs and none of them had concomitant biologic therapy. In this group of patients, the most common type of infection was bacterial (72.7%), followed by viral (9.1%) including a patient with SARS-CoV-2 infection. Conclusion: Hospital administrative databases can be a useful source of information for monitoring outcomes that generate significant morbidity and mortality in patients with SLE, in the group of patients in whom infections were documented, bacterial infections were the most frequent. The most documented clinical findings were leukopenia, systemic steroid therapy, and concomitant disease activity.

Objetivo: Estimar la frecuencia de las infecciones y describir su patrón de presentación en pacientes con diagnóstico de lupus eritematoso sistémico (LES) atendidos en el Hospital Militar Central (Homil) en Bogotá, Colombia. Métodos: Se realizó un estudio descriptivo en el que se utilizó una base de datos administrativa del Hospital Military se empleó un algoritmo validado que clasificó a los pacientes con LES en las bases de datos administrativas. La infección se definió a partir de los códigos CIE-10 o por la búsqueda en la base de datos de la prescripción de antibióticos; adicionalmente, en las historias clínicas del grupo de pacientes en los que se documentaron infecciones, se revisaron algunas variables relacionadas con el estado de LES durante el evento de la infección. Resultados: Se identificaron 237 pacientes con LES, cuya edad media fue de 41,9 años (IC 29,0-54.3), el 80% eran mujeres y el 97,7% usaba medicamentos antirreumáticos modificadores de la enfermedad (DMARD) convencionales. De estos 237 pacientes, 22 (9,4%) cumplieron con la definición operativa de infección; en este grupo la edad media fue de 44,3 anos (DE = 16.4). Los 22 pacientes recibieron DMARD convencionales y ninguno recibió terapia biológica concomitante. En este grupo, el tipo de infección más común fue la bacteriana (72,7%), seguida de la viral (9,1%), incluido un paciente con infección por SARS-CoV-2. Conclusiones: Las bases de datos administrativas hospitalarias pueden ser una fuente útil de información para el seguimiento de los eventos que generan una morbimortalidad significativa en los pacientes con LES. En el grupo de pacientes en los que se documentaron infecciones, las infecciones bacterianas fueron las más frecuentes y los hallazgos clínicos más comúnmente documentados fueron la leucopenia, la terapia con esteroides sistémicos y la actividad de la enfermedad concomitante.

Evaluation of the adipokine profile (adiponectin, resistin, adipsin, vaspin, and leptin) in patients with early rheumatoid arthritis and its correlation with disease activity.

Introduction: Adipokines may play a role in the early stages of rheumatoid arthritis. This study evaluated the performance of adipokines in a Colombian population with early rheumatoid arthritis and its relationship with disease activity. Material and methods: A cross-sectional study evaluated serum adipokine levels (adiponectin, resistin, adipsin, vaspin, and leptin) in patients with early rheumatoid arthritis (eRA), evaluating demographic and clinical variables, along with a control group matched by age and gender. A factorial analysis was performed using principal components analysis (PCA), and a Spearman correlation analysis was performed. Similarly, a cut-off point for serum levels is proposed based on the receiver operating characteristic (ROC) curve between eRA and controls and sensitivity analysis. Results: Fifty-one eRA subjects were included; there were 41 women. The body mass index (BMI) was 25.12 ±3.8. A statistically significant correlation was identified between adipsin, BMI, and RAPID3. Vaspin and leptin were correlated with BMI. Resistin levels were higher in patients with RAPID3 near remission (p = 0.041), and adiponectin, vaspin, and leptin levels were lower in patients with DAS28 ESR in remission (p = 0.033, p = 0.012, and p = 0.017, respectively). Principal components analysis in component 1 adipokines as adipsin and leptin with BMI and RAPID3 as disease activity index are grouped. Moreover, component 2 had a strong relation between ESR and CRP with an inverse correlation with cholesterol levels and vaspin. A cut-off point was established for each adipokine, thus identifying the best performance for leptin levels greater than 0.58 ng/ml with a sensitivity of 76.5% and specificity of 74.5%. Conclusions: Adipokine levels are relevant in eRA, especially with disease activity indexes. Resistin levels were higher in patients with an activity index near remission. Otherwise, adiponectin, vaspin, and leptin levels were lower in patients with low activity indexes. RAPID3 correlated with adipsin. It is complementary to the previously published analysis of adipokines.

Frequency and distribution of Blastocystis sp. subtypes in patients with spondyloarthritis in Bogotá, Colombia.

Although Blastocystis sp. is one of the most prevalent intestinal parasites worldwide, its role as a pathogen remains unclear. The use of molecular techniques to assess the genetic heterogeneity of Blastocystis sp. has become important to understand its function in some intestinal pathologies and if it is a key component of intestinal microbiota. Spondyloarthritis is a group of immune-mediated autoinflammatory diseases in which microbial dysbiosis in the gut (including parasites, bacteria and fungi) and intestinal inflammation are common features apparently associated with the pathophysiology of these disorders. This study included 74 patients diagnosed with spondyloarthritis and 57 systemically healthy individuals (included as controls), who were screened for intestinal parasites. Blastocystis sp. was detected in 68% and 73% of the patients with spondyloarthritis and controls, respectively. In faecal samples positive for Blastocystis sp., an 18S rRNA gene fragment of Blastocystis sp. was amplified and sequenced to identify their genetic sub-types. Patients with spondyloarthritis showed similar frequencies of ST1, ST2 and ST3 subtypes of Blastocystis sp. (30% each). The same subtypes were observed in controls, wherein almost 60% of the samples showed ST3. In addition, ST6 was found only in one sample from each group. ST1 subtype showed the greatest genetic variability. Although the same subtypes were detected in both patients with spondyloarthritis and controls, subtype prevalence studies conducted in Colombia indicate an association between ST3 and individuals with irritable bowel syndrome. This opens an interesting research avenue to further study of the epidemiology of Blastocystis sp. and its possible relationship with intestinal conditions in immunocompromised patients.

Estimation of Prevalence and Incremental Costs of Systemic Lupus Erythematosus in a Middle-Income Country Using Machine Learning on Administrative Health Data.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that may cause physical and functional disability. The objective of this study is to measure prevalence and estimate incremental cost of SLE treatment using information from administrative databases in Colombia. METHODS: We use data from the patients on the Colombian contributive health system with a period of study from 2015 to 2017. The incremental cost of SLE is estimated using a matched study by propensity score and multivariate balance of covariates. To reduce the effect of possible specification problems, we use Extreme Gradient Boosting, a flexible machine learning algorithm. We use paired t statistical comparison and Bootstrap to validate the robustness of the method. In addition, we use a machine learning regression approach on the cost of control patients to achieve double robustness and compare the results. RESULTS: SLE prevalence ranges between 41.65 and 54.47 (cases/100 000), which is lower than other Latin American countries. Using the operative definition of SLE, 5527 patients were selected. The potential control sample was composed of 1 942 253 patients. The total annual direct estimated cost per patient was US $2172. Adjusted incremental cost was US $1662. Considering 4 severity classes of SLE, the cost ranges from US $8823 for severe to US $447 for mild cases. CONCLUSIONS: Incremental costs of SLE in Colombia are similar to those from other middle-income countries. Compared with high-income countries, the cost is lower; nevertheless, if it is calculated proportional to the per capita health expenditure, it is comparable.

Frecuencia de ANA/DFS70 en familiares de pacientes con artritis reumatoide comparados con pacientes con artritis reumatoide y población sana y su asociación con el estado de salud / Frequency of ANA/DFS70 in Relatives of Patients with Rheumatoid Arthritis Compared to Patients with Rheumatoid Arthritis and a Healthy Population, and its Association with Health Status

Introducción: Los ANA/DFS70 han atraído el interés por su frecuencia en individuos sin evidencia clínica de enfermedad reumática sistémica autoinmune, no se han evaluado grupos de riesgo genético para artritis reumatoide (AR). Objetivo: Determinar la frecuencia de ANA y ANA/DFS70 en familiares consanguíneos (FC) de AR comparada con pacientes con AR temprana (ARt) e individuos control y su asociación con el estado de salud. Metodología: Estudio de corte transversal con componente analítico. Análisis de 60 pacientes ARt, 60 FC y 120 individuos control pareados por edad y sexo. Se analizaron ANA-HEp2 y ANA/DFS70. Establecieron las frecuencias absolutas y relativas y asociaciones con modelos de regresión logística, con un nivel de significación del 95%. Resultados: ANA de 43% en ARt, 30% en FC y 25,8% en individuos control a título 1:80. El patrón granular fino denso por Hep2 convencional se encontró en el 12,9% de las muestras positivas y el 1,66% del total de muestras. En ANA/DFS70 (+) en 1,66% en FC y 2,5% de individuos control, representando el 75% de la muestras positivas y el 1,25% del total de las muestras. No hubo detección de ANAS-DFS70 en pacientes con ARt. En ARt hubo asociación entre la presencia de ANA y articulaciones inflamadas (p=0,02), PCR (p=0,01), DAS28PCR (p=0,03) y HAQ (p=0,04). Asociación entre ANA y PCR elevada (p=0,05) en FC. En individuos control entre ANA y articulaciones dolorosas (p=0,02). En individuos ANA-DFS70 observamos asociación con VSG normal p=0,032, FR (-), p=0,044 y ausencia de articulaciones dolorosas, p=0,039. Conclusiones: La frecuencia de ANA/DFS70 en los grupos estudiados fue baja, ninguno de los pacientes con ARt fue positivo. Se confirma la presencia de ANA/DFS70 solo en individuos sanos sistémicamente.(AU)

Introduction: DFS70 ANAs have attracted interest due to their frequency in individuals with no clinical evidence of systemic autoimmune rheumatic disease, groups with genetic risk for rheumatoid arthritis (RA) were not assessed. Objective: To determine the frequency of ANA and DFS70 ANA in blood relatives (BR) of people with RA compared to patients with early RA (ERA), and control individuals, and its association with health status. Methodology: A cross-sectional study with an analytical component. Sixty ERA patients, 60 BR and 120 control individuals paired by age and sex were studied. Hep2-ANA and DFS70 ANA were studied. The absolute and relative frequencies and associations were established using logistic regression models, with a significance level of 95%. Results: 43% ANA in ERA, 30% in BR, and 25.8% in control individuals 1:80. The fine dense granular pattern based on conventional Hep2 was found in 12.9% of the positive samples, and 1.66% of the total samples. There was no detection of DFS70 ANAs in patients with ERA. In ERA there was an association between the presence of ANA and inflamed joints (p=.02), CRP (p=.01), DAS28CRP (p=.03) and HAQ (p=.04). There was an association between ANA and elevated CRP (p=.05) in the BR. In the control individuals, there was an association between ANA and painful joints (p=02). In DFS70 ANA individuals we observed an association between a normal ESR p=.032, BR (-), p=.044 and absence of painful joints, p=.039. Conclusions: The frequency of DFS70 ANA in the groups studied was low, none of the patients with ERA was positive. The presence of DFS70 ANA was only confirmed in systemically healthy individuals.(AU)

Frequency of ANA/DFS70 in Relatives of Patients with Rheumatoid Arthritis Compared to Patients with Rheumatoid Arthritis and a Healthy Population, and its Association with Health Status. / Frecuencia de ANA/DFS70 en familiares de pacientes con artritis reumatoide comparados con pacientes con artritis reumatoide y población sana y su asociación con el estado de salud.

INTRODUCTION: DFS70 ANAs have attracted interest due to their frequency in individuals with no clinical evidence of systemic autoimmune rheumatic disease, groups with genetic risk for rheumatoid arthritis (RA) were not assessed. OBJECTIVE: To determine the frequency of ANA and DFS70 ANA in blood relatives (BR) of people with RA compared to patients with early RA (ERA), and control individuals, and its association with health status. METHODOLOGY: A cross-sectional study with an analytical component. Sixty ERA patients, 60 BR and 120 control individuals paired by age and sex were studied. Hep2-ANA and DFS70 ANA were studied. The absolute and relative frequencies and associations were established using logistic regression models, with a significance level of 95%. RESULTS: 43% ANA in ERA, 30% in BR, and 25.8% in control individuals 1:80. The fine dense granular pattern based on conventional Hep2 was found in 12.9% of the positive samples, and 1.66% of the total samples. There was no detection of DFS70 ANAs in patients with ERA. In ERA there was an association between the presence of ANA and inflamed joints (p=.02), CRP (p=.01), DAS28CRP (p=.03) and HAQ (p=.04). There was an association between ANA and elevated CRP (p=.05) in the BR. In the control individuals, there was an association between ANA and painful joints (p=02). In DFS70 ANA individuals we observed an association between a normal ESR p=.032, BR (-), p=.044 and absence of painful joints, p=.039. CONCLUSIONS: The frequency of DFS70 ANA in the groups studied was low, none of the patients with ERA was positive. The presence of DFS70 ANA was only confirmed in systemically healthy individuals.

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project).

OBJECTIVE: To develop new composite disease activity indices for psoriatic arthritis (PsA). METHODS: Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). RESULTS: 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index>10) both nonparametric and AUC curve statistics were nonsignificant for all measures. CONCLUSIONS: Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.