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Increased global longevity requires a re-evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in e.g. multimorbidity, polypharmacy, hospitalisation, and problems in medication management, it is increasingly acknowledged that re-evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) "Geriatric Strategy", in 2017, the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties on the urgency to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and the drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice.

Additional file 2: Figure S2. (a) QQ plot showing the observed versus expected SNPs p-value distribution. After the mixed model approach, the inflation factor λ is equal to 0.93. The QQ plot also shows the empirical genome-wide significance threshold (indicated by a red line and its corresponding –log10 value equal to 5.14) and empirical 95% confidence intervals (CI95) (indicated by solid grey lines). (b) Manhattan plot showing a peak of association on CFA11 (p-valueraw = 9.9 × 10− 6).

Additional file 5: Figure S5. Manhattan plot after conditioning the GWA analysis for the fine-mapping top SNP genotype.

Additional file 4: Figure S4. (a) QQ plot showing the observed versus expected SNPs p-value distribution of the final complete dataset including both GWA and fine-mapping SNPs. After the mixed model approach, the inflation factor λ is equal to 0.97. The QQ plot also shows the empirical genome-wide significance threshold, p-value = 5.4 × 10− 6 (indicated by a red line and its corresponding –log10 value equal to 5.27), and empirical 95% confidence intervals (CI95) (indicated by solid grey lines). (b) Manhattan plot confirming the detection of a peak of association on CFA11 (p-valueraw = 5.7 × 10− 6) during the fine-mapping experiment.

Additional file 1: Figure S1. (a) MDS plot showing the sample set before quality control (QC). The red circle highlights the outlier samples (n = 6). The black arrow indicates the outlier sample (n = 1) with the standard coat color. (b) MDS plot showing the sample set after quality control (QC).

Additional file 6: Figure S6. The 3-primer design for deletion genotyping. Primers NF11 and NR12 give a PCR product (906 bp) from only the allele without the deletion. Primers NF3 and NR12 give PCR products from both alleles without the deletion (~ 11,000 bp) and with the deletion (1038 bp). However, using the PCR elongation optimal for amplifying up to 1 kbp produced only the two shorter fragments (906 and 1038 bp), enabling the genotype determination during the subsequent separation on the agarose gel.

Additional file 8: Table S2. Number of SNPs that were successfully pooled for high-throughput re-genotyping in all the samples (Pooled Variants), number of SNPs that were subsequently genotyped with success (Successfully genotyped variants), and criteria for variant selection (Functional Category): Conserved elements (SNPs overlapping conserved elements with SiPhy LOD-score higher than 7 based on 29 mammals conservation scores), VEP (SNPs predicted to have an effect on the amino acid sequence according to the Variant Effect Predictor webtool analysis), Antisense/Protein coding transcripts (SNPs overlapping predicted antisense and protein coding transcripts), Promoter (SNPs overlapping predicted promoters of genes located in the associated genomic region), AF difference (SNPs with high allele frequency differences between LC cases and LC controls), SNPChip (control SNPs included in the Illumina SNPChip for the genotype concordance check between the two experiments), Fill the gaps (SNPs located in the regions of low coverage in the extended region of association).

The domestic dog, with its unique genetic structure formed by domestication and recent breed creation, has been proven to be an excellent model for mapping disease genes. In this thesis, we use the dog as a model to investigate the prevalence and genetic background of canine lymphocytic thyroiditis (CLT), one of the most common immune related diseases in dogs. The canine phenotype has been carefully characterized and suggests a strong comparative value to human Hashimoto’s disease because of similar etiology, clinical signs and disease progression. Therefore, our aim was to gain increased knowledge about CLT and its relevance to human autoimmune thyroid disease, to benefit both dogs and humans. In our first study (paper I) we screened two birth cohorts (3-4 and 6-7 years old, respectively) for elevated serum levels of autoantibodies to thyroglobulin (TgAA) and thyroid stimulating hormone (TSH) and could estimate a very high prevalence of CLT in the giant schnauzer and the hovawart breeds. Next, we aimed at unraveling the genetic background of CLT in the same breeds, using two different approaches; a candidate gene approach followed by a genome-wide association analysis. Using the first approach we obtained evidence that DLA class II polymorphisms can function both as a genetic risk factor predisposing for the disease as well as a protective factor against the disease. Using genome wide association we identified two additional strong susceptibility loci located on chromosome 11 and X. Both regions harbour genes with known immune-regulatory functions and implicates three genes involved in NF-κB pathway. Given the reported role of NF-κB in many human autoimmune diseases, our results suggest CLT as an excellent genetic model for human thyroiditis.