Low levels of serotonin , a neurotransmitter in the brain, have been linked to depression . High levels of estrogen, as in first-generation COCPs, and progestin, as in some progestin-only contraceptives, have been shown to lower the brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin. This observation, along with some small research studies  have inspired speculation that the pill causes depression. In 2016, a large Danish study of one million women showed that use of COCPs, especially among adolescents, was associated with a statistically significantly increased risk of subsequent depression, although the sizes of the effects are small (for example, % of the women who took any form of oral birth control were prescribed anti-depressants for the first time, compared to % of women in the control group). 
Scientists continue to work on better ways to design, conduct and evaluate non-randomized (., observational) studies to assess how well flu vaccines work. CDC has been working with researchers at universities and hospitals since the 2003-2004 flu season to estimate how well flu vaccine works through observational studies using laboratory-confirmed flu as the outcome. These studies currently use a very accurate and sensitive laboratory test known as RT-PCR (reverse transcription polymerase chain reaction) to confirm medically-attended flu virus infections as a specific outcome. CDC’s studies are conducted in five sites across the United States to gather more representative data. To assess how well the vaccine works across different age groups, CDC’s studies of flu vaccine effects have included all people aged 6 months and older recommended for an annual flu vaccination. Similar studies are being done in Australia, Canada and Europe. More recently, CDC has set up a second network the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) that looks at how well flu vaccine protects against flu-related hospitalization among adults aged 18 and older.