Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

Proteomics of toxic oil syndrome in humans: Phenotype distribution in a population of patients.

OBJECTIVES: Toxic oil syndrome (TOS) is a disease that appeared in Spain in 1981. Epidemiological work traced the origin to the ingestion of aniline-adulterated rapeseed oil, fraudulently marketed and sold as edible oil. It affected more than 20,000 people with over 400 deaths in the first 2 years. In 2001 evidence was presented that genetic factors could play a role in the susceptibility of individuals to the disease. Thus, a prospective study on the differences in gene expression in sera between control versus TOS-affected populations, both originally exposed to the toxic oil, was undertaken in our laboratory. METHODS: Differential protein expression was analyzed by two-dimensional electrophoresis (2-DE). Problems related with serum analysis by 2-DE were addressed to improve protein detection in the gel images. Three new commercial systems for albumin depletion were tested to optimize the detection of minor proteins. The use of nonionic reductants or the presence of thiourea in the gels, were also tested. RESULTS: From the resulting optimized images, a group of 329 major gel spots was located, matched and compared with serum samples. Thirty-five of these protein spots were found to be under- or over-expressed in TOS patients (threefold increase or decrease). Proteins in these spots were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) peptide map fingerprinting and database search. Several haptoglobin (Hp) isoforms were found to be differentially expressed, showing expression phenotypes that could be related with TOS. Resolution of the homologous α-1s and α-1f chains, with a mass difference of only 0.043Da, was obtained after guanidation of the protein with O-methylisourea. We applied this procedure to the study of the distribution of the Hp alleles HP(2), HP(1s) and HP(1f) in control versus TOS-affected populations. The MALDI-TOF proteotyping method was validated by a parallel analysis of the serum samples by 2-DE. CONCLUSIONS: Data obtained from 54 TOS cases and 48 controls indicate significant differences in the distribution of Hp phenotypes in the two populations. Haptoglobin phenotypes have been reported to have biological and clinical consequences and have been described as risk factors for several diseases. Consequently, it was concluded that haptoglobin polymorphism could play a role in TOS.

High prevalence of cardiovascular risk in patients with toxic oil syndrome: a comparative study using the general Spanish population.

BACKGROUND: The objective of this study was to compare current prevalence of major cardiovascular risk factors (CRF) between a cohort of patients affected by the toxic oil syndrome (TOS) epidemic, which occurred in Spain in 1981, and the unaffected Spanish population. METHODS: This was a case-referent study covering 1276 TOS cases and a referent population of 2843 (aged 35-65 years) using data collected from 1996 to 2003. Study variables were high blood pressure, hyperglycemia, dyslipemia, obesity, and metabolic syndrome. Smoking habit, alcohol intake, family and personal history of ischemic heart disease, as well as a personal history of cerebrovascular disease were also assessed in TOS patients. RESULTS: Compared to the general population, TOS patients registered a threefold rise in prevalence of diabetes, a 2.57-fold increase in hypertension, a 1.38-fold increase in total hypercholesterolemia, a 1.20-fold increase in hyper-LDL-cholesterolemia, and a high prevalence of metabolic syndrome (35% versus 25%). Nevertheless, the prevalence of hypo-HDL-cholesterolemia was significantly lower in those affected by TOS. No differences were found for other CRFs. CONCLUSION: Compared to the general population, cases display a much higher prevalence of all major CRFs. However, an increase in HDL-cholesterol protective factor is in evidence for the first time.

Proteotyping of human haptoglobin by MALDI-TOF profiling: Phenotype distribution in a population of toxic oil syndrome patients.

Toxic oil syndrome (TOS) is a disease that appeared in Spain in 1981 as a consequence of the ingestion of an aniline-adulterated oil illegally marketed as edible. TOS affected more than 20 000 people and produced over 400 deaths in the first 18 months after the outbreak. There is evidence that genetic factors could play a role in the susceptibility of individuals towards the disease. Recently, we suggested that haptoglobin (Hp) polymorphism could also play a role in TOS. To provide a rapid method for high-throughput Hp phenotyping, we developed a two-step MALDI-TOF procedure that allows specific identification of the three common Hp alpha chains. Resolution of the homologous alpha-1s and alpha-1f chains, which have a mass difference of only 0.043 Da, is obtained after guanidination of the protein with O-methylisourea. We applied this procedure to the study of the distribution of the Hp alleles HP(1s), HP(1f), HP(2) in a control versus a TOS-affected population, both originally exposed to the toxic oil. The MALDI-TOF proteotyping method was validated by a parallel analysis of the serum samples by 2-DE. Data obtained from 54 TOS cases and 48 control individuals indicate significant differences in the distribution of Hp phenotypes in the two populations.

[Diagnostic performance of echocardiography in the follow-up of patients with toxic oil syndrome]. / Rendimiento diagnóstico de la indicación de ecocardiografía en el seguimiento de los pacientes con "sindrome de aceite tóxico".

INTRODUCTION AND OBJECTIVES: Toxic oil syndrome is an epidemic, multisystemic disease that appeared in Spain in 1981, and was caused by the consumption of rapeseed oil denatured with 2% aniline. The disease is similar to eosinophilia-myalgia syndrome. One of the cardiovascular disorders caused by this syndrome is pulmonary hypertension. We conducted a study to assess the validity of our indications for echocardiography in the follow-up of cardiovascular disorders in patients with this disease. PATIENTS AND METHOD: These patients are followed at our center with a standardized protocol for annual check-ups. From December 1997 through July 2002, a total of 1993 patients were examined. In this period we performed a total of 487 echocardiographic studies in 424 patients. The clinical records were reviewed to assess the indications for echocardiography according to the most recent guidelines for the clinical application of echocardiography of the American College of Cardiology and American Heart Association, and the indications were grouped into several categories. The diagnosis was recorded from the cardiologist's reports at the hospital where echocardiography was done. We calculated the sensitivity, specificity and positive likelihood ratio. RESULTS: 67% of the echocardiographic examinations were indicated to investigate possible pulmonary hypertension. About one-tenth of the studies (476 studies, 9.9%) led to a diagnosis of pulmonary hypertension. Sensitivity was highest (83%) for suspected pulmonary hypertension. Specificity was very high for most of the other indications. CONCLUSIONS: This study does not allow us to draw general conclusions about the cardiovascular disorders associated with toxic oil syndrome. However, echocardiography appears to be a good follow-up technique to diagnose complications such as pulmonary hypertension in these patients.

Carpal tunnel syndrome. A new feature in the natural history of TOS?

OBJECTIVE: To ascertain whether carpal tunnel syndrome (CTS) in patients affected with toxic oil syndrome (TOS) is associated with conditions and diseases considered risk factors for CTS in the general population and/or with certain clinical manifestations of TOS. METHODS: We conducted a case-control study to compare 89 TOS patients residing in Madrid diagnosed with CTS from 1981 through July 2001 (cases) against 638 TOS patients not affected with CTS (controls). Risk factors for CTS and clinical manifestations of TOS were analyzed. RESULTS: Multivariate logistic regression analysis yielded the following odds ratios (95% confidence interval): 3.32 (1.47-7.50) for TOS-related neuropathy; 2.85 (1.14-7.13) for TOS-related thromboembolic events; 2.63 (1.36-5.06) for female gender; 0.43 (0.24-0.80) for TOS-related scleroderma; 0.26 (0.12 0.59) for smoking; and, in women, 2.53 (1.06-5.70) for fibrositis and 1.84 (1.04-3.20) for miscarriages. CONCLUSION: Our study findings support the hypothesis that CTS in TOS patients is more linked to certain clinical manifestations of TOS, mainly neuropathy, than to conditions and diseases considered risk factors for CTS in the general population.

[Prevalence of cardiovascular risk factors in a cohort of affected by the toxic oil syndrome]. / Prevalencia de factores de riesgo cardiovascular en una cohorte de afectados por el síndrome del aceite tóxico.

BACKGROUND AND OBJECTIVE: During the first stages of the toxic oil syndrome (TOS), elevations of the blood pressure as well as increases in the cholesterol, glucose and triglycerides levels were reported. Here we analyze these cardiovascular risk factors in the chronic phase of the illness and their distribution according to the severity of the illness. We also compare them with those found in the general population. PATIENTS AND METHOD: We studied a sample of 1,862 individuals aged between 35 and 65 years. A medical examination was performed in each and blood pressure, weight, height, tobacco consumption, cholesterol, glucose and triglycerides levels were measured. RESULTS: The prevalence of high blood pressure (>140/90 mmHg) was 46.1% and the prevalence of diabetes mellitus (>126 mg/dl) was 9.1%. The prevalence of obesity (BMI>30) was 24.9%. 11.8% of patients had hypertriglyceridemia (>200 mg/dl) and 19.8% had hypercholesterolemia (>250 mg/dl). 37.9% were smokers. The standardized prevalence rate (SPR) of high blood pressure was 1.35 (95% CI, 1.28-1.44); tobacco consumption SPR=1.27 (95% CI, 1.20-1.36); hypercholesterolemia SPR=1.10 (95% CI, 1.01-1.21). The prevalence of risk factors was higher among the most seriously affected subjects. CONCLUSIONS: The chronic phase of TOS is characterized by a high prevalence of cardiovascular risk factors, which was significantly higher than that expected in the general population.

Characteristics of disability and handicap among Toxic Oil Syndrome (TOS) cohort patients: a cross-sectional study, 17 years after the original food intoxication.

PURPOSE: In 1981, a progressive multi-systemic disease called Toxic Oil Syndrome (TOS) appeared in Spain as an epidemic that affected 20,000 people. The International Classification of Impairments, Disabilities and Handicaps (ICIDH) was chosen to characterize the health status of patients more severely affected by TOS. METHODS: A random sample of 292 with permanent disability was selected. Disability was assessed with a questionnaire based on ICIDH and the Stanford Health Assessment Questionnaire. Handicap was measured using London Handicap Scale. Distributions of the proportions and 95% confidence intervals for disabilities, handicaps were calculated and stratified by dimensions, age and sex. The chi2 test was used for inter-group comparisons. RESULTS: Two hundred and fourteen patients were interviewed. Mobility-related and behaviour disabilities were most prevalent. Disability rose with age and was higher among women, except for behaviour disabilities which were more frequent in young men. Mean handicap score was 78.0 +/- 12.7. Handicap dimensions most affected were physical independence and economic self-sufficiency. CONCLUSIONS: The health profile of the population hardest hit by TOS is characterized by the presence of important functional and psychosocial disabilities that limit performance of daily living activities and social role, and are in accord with the handicap that such persons suffer.

Prevalencia de factores de riesgo cardiovascular en una cohorte de afectados por el síndrome del aceite tóxico / Prevalence of cardiovascular risk factors in a cohort of affected by the toxic oil syndrome

FUNDAMENTO Y OBJETIVO: En las primeras fases del síndrome del aceite tóxico (SAT) se ha descrito la elevación de las cifras de la presión arterial, de la concentración de colesterol, de la glucemia y de los triglicéridos. Hoy las enfermedades cardiovasculares son su principal causa de muerte. Pretendemos describir los factores de riesgo cardiovascular en la fase crónica de la enfermedad y su distribución según gravedad de la enfermedad, y compararlos con la población general. PACIENTES Y MÉTODO: Se ha estudiado a 1.862 sujetos con edades comprendidas entre 35 y 65 años. Se les realizó una exploración médica y se midieron las variables presión arterial, peso, talla, tabaquismo, colesterol, glucemia y triglicéridos. RESULTADOS: La prevalencia de hipertensión arterial (definida por presión arterial superior a 140/90 mmHg) fue del 46,1 por ciento, y la de diabetes mellitus (definida por glucemia mayor de 126 mg/dl), del 9,1 por ciento. La prevalencia de obesidad (índice de masa corporal superior a 30 kg/m2) fue del 24,9 por ciento; la de hipertrigliceridemia (concentración de triglicéridos superior a 200 mg/dl), del 11,8 por ciento, y la de hipercolesterolemia (concentración de colesterol mayor de 250 mg/dl), del 19,8 por ciento. El porcentaje de fumadores fue del 37,9 por ciento. La razón de prevalencia estandarizada para hipertensión fue de 1,35 (intervalo de confianza [IC] del 95 por ciento, 1,28-1,44), para tabaquismo de 1,27 (IC del 95 por ciento, 1,20-1,36) y para hipercolesterolemia de 1,10 (IC del 95 por ciento, 1,01-1,21).La prevalencia de factores de riesgo fue mayor en los enfermos graves. CONCLUSIONES: La fase crónica del SAT se caracteriza por una elevada prevalencia de factores de riesgo cardiovascular, mayor de lo esperado para la población general (AU)

Immunoglobulin and autoantibody responses in MRL/lpr mice treated with 'toxic oils'.

The toxic oil syndrome (TOS) occurred in Spain in 1981 as a result of ingestion of oil mixtures containing aniline-denatured rapeseed oil. The disease afflicted almost 20000 people, resulted in more than 400 deaths, and mimicked an autoimmune disease in all patients. Phenilamine-propanediol (PAP) has been implicated as a possible etiologic agent of TOS but absence of an acceptable animal model to evaluate the autoimmune potential of the 'case oil' has hindered identification of the actual etiologic agent(s). The purpose of this study was twofold; (1) to develop an animal model of human disease to investigate the immunological etiology and pathogenesis of TOS and (2) to determine if the 'case oil' responsible for TOS and/or two synthesized oils either induced or exacerbated the systemic autoimmune disease that occurs spontaneously in the MRL/lpr mouse. The oils tested were a denatured rapeseed oil collected from a family (case oil) who were affected by the TOS (CO756), a rapeseed oil denatured with 2% aniline and enriched with a mixture of diesters of PAP (RSD), and a rapeseed oil denatured with 2% aniline but contained no diesters of PAP (RSA). Female MRL/lpr mice, 7 weeks of age, received orally either an undiluted (neat) or a 1:10 diluted dose of each test oil, canola oil (oil control), water (nai;ve control), or 50-ppm mercury (positive control). Half of each group was sacrificed after 5 weeks of exposure and the remaining mice after 10 weeks of exposure. Serum IgG1, IgG2a, IgE isotypes and antinuclear (ANA), collagen type II, histone, single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and Sm autoantibody concentrations were determined after 5 and 10 weeks of exposure. The oils did not significantly affect the concentrations of the serum immunoglobulins, although a shift in the IgG1:IgG2a ratio towards IgG1 was noted from 12 to 17 weeks of age (5-10 weeks of treatment). The oils did however stimulate the systemic autoimmune response. The RSD neat treatment resulted in a nonsignificant but noted increase in autoantibodies to collagen (10 weeks), histone (10 weeks) and dsDNA (5 and 10 weeks). CO756 neat increased the serum levels of ANA (5 weeks), collagen (5 weeks) and dsDNA (5 and 10 weeks). The RSA 1:10 dilution increased ssDNA and dsDNA autoantibodies at 5 weeks. The results suggest that PAP is an active principle of these noted responses. These data, coupled with the toxicology and pathology data from this study (Toxicol. Path. 29 (2001) 630), revealed that the three oils incited induction of the lymphoproliferative syndrome and that the two oils containing PAP induced and enhanced the systemic autoimmune response that develops spontaneously at an early age in the MRL/lpr mouse. There was also a positive correlation noted between serum autoantibody concentrations and progression of the idiopathic autoimmune syndrome in the MRL/lpr mouse.